As we close out the first quarter of 2025, we are excited to present this month’s Editors’ Picks. March’s selections from the editors of the 10 American Association for Cancer Research (AACR) journals highlight studies on the immunostimulatory impact of extracellular vesicles secreted by senescent cancer cells, a molecule that might protect cells from ultraviolet radiation’s harmful effects, strategies for manipulating mesenchymal-like cancer cells, and more. As always, these studies will be freely available for a limited time. 

Journal: Blood Cancer Discovery 

The Crossroads of Clonal Evolution, Differentiation Hierarchy, and Ontogeny in Leukemia Development 

Transformative technologies to sequence tumor genomes at large scale and single-cell resolution have exposed the repertoire of genetic alterations that are present in leukemia genomes, the timing of their acquisition, and patterns of their co-occurrence. In parallel, single-cell multiomics technologies are allowing us to map the differentiation paths and hierarchical structures of malignant cells and giving us a glimpse into hematopoietic development in prenatal life. We propose that interrogating how the genetic evolution, differentiation hierarchy, and ontogeny of malignant myeloid cells intersect with each other, using new experimental systems and multimodal technologies, will fuel the next generation of research breakthroughs. 

Significance: In recent years, remarkable technological advances have illuminated aspects of the pathogenesis of myeloid malignancies—yet outcomes for patients with these devastating diseases have not significantly improved. We posit that a synthesized view of the three dimensions through which hematopoietic cells transit during their healthy and diseased life—clonal evolution, stem cell hierarchy, and ontogeny—promises high yields in new insights into disease pathogenesis and new therapeutic avenues. 

This article was featured on the cover of the March issue. 

Journal: Cancer Discovery 

PKN2 Is a Dependency of the Mesenchymal-like Cancer Cell State 

Cancer cells exploit a mesenchymal-like transcriptional state (MLS) to survive drug treatments. Although the MLS is well characterized, few therapeutic vulnerabilities targeting this program have been identified. In this study, we systematically identify the dependency network of mesenchymal-like cancers through an analysis of gene essentiality scores in ∼800 cancer cell lines, nominating a poorly studied kinase, PKN2, as a top therapeutic target of the MLS. Coessentiality relationships, biochemical experiments, and genomic analyses of patient tumors revealed that PKN2 promotes mesenchymal-like cancer growth through a PKN2−SAV1−TAZ signaling mechanism. Notably, pairing genetic PKN2 inhibition with clinically relevant targeted therapies against EGFR, KRAS, and BRAF suppresses drug resistance by depleting mesenchymal-like drug-tolerant persister cells. These findings provide evidence that PKN2 is a core regulator of the Hippo tumor suppressor pathway and highlight the potential of PKN2 inhibition as a generalizable therapeutic strategy to overcome drug resistance driven by the MLS across cancer contexts. 

Significance: This work identifies PKN2 as a core member of the Hippo signaling pathway, and its inhibition blocks YAP/TAZ-driven tumorigenesis. Furthermore, this study discovers PKN2−TAZ as arguably the most selective dependency of mesenchymal-like cancers and supports specific inhibition of PKN2 as a provocative strategy to overcome drug resistance in diverse cancer contexts. 

This article was highlighted and featured on the cover of the March issue, in addition to a commentary related to this study. 

Journal: Cancer Epidemiology, Biomarkers & Prevention 

Circulating Estrogen Metabolites and Risk of Breast Cancer among Postmenopausal Women in the Nurses’ Health Study 

Background: Estradiol and estrone are well-established risk factors for postmenopausal breast cancer. Experimental evidence suggests that specific estrogen metabolites, produced via irreversible hydroxylation of estrone and estradiol at position 2 or 16, may independently influence carcinogenesis. 

Methods: We performed a nested case–control study of breast cancer (328 breast cancer cases; 639 controls) among postmenopausal women within the Nurses’ Health Study to examine the role of estrogens and estrogen metabolites (jointly referred to as EM). Plasma concentrations of each EM (unconjugated + conjugated forms) were measured by LC-MS/MS. Multivariable conditional logistic regression, adjusting for breast cancer risk factors, estimated relative risks (RR) and 95% confidence intervals of breast cancer across quintiles of individual EM, EM pathways, and pathway ratios. Associations by estrogen receptor (ER) and progesterone receptor (PR) status were analyzed by unconditional logistic regression. 

Results: Estradiol and estrone were strongly associated with increased breast cancer risk [estradiol: RRQ5 vs. Q1 (95% confidence interval) = 2.64 (1.64–4.26); estrone: 2.78 (1.74–4.45); both P-trends <0.001]. The 2-hydroxylation pathway was strongly associated with risk [RRQ5 vs. Q1 = 3.09 (1.81–5.27); P-trend <0.001] and remained so after adjusting for unconjugated estradiol [RRQ5 vs. Q1 = 2.23 (1.25–3.96); P-trend = 0.01]. Although the 16-hydroxylation pathway was modestly associated with risk [RRQ5 vs. Q1 = 1.62 (1.03–2.54); P-trend = 0.01], the association was attenuated after unconjugated estradiol adjustment [RRQ5 vs. Q1 = 1.24 (0.77–1.99); P-trend = 0.19]. Similar positive associations with the 2-pathway and 16-pathway were observed for ER+/PR+ and ER−/PR− tumors. 

Conclusions: In this cohort of postmenopausal women, 2-hydroxylation of estrone and estradiol was associated with increased breast cancer risk, independent of unconjugated estradiol. 

Impact: These results highlight the need to revisit the role of estrogen metabolism in breast cancer etiology and prevention. 

This article was highlighted in the March issue, in addition to a commentary related to this study. 

Journal: Cancer Immunology Research 

NI-3201 Is a Bispecific Antibody Mediating PD-L1–Dependent CD28 Co-stimulation on T Cells for Enhanced Tumor Control 

Despite advances in cancer immunotherapy, such as targeting the PD-1/PD-L1 axis, a substantial number of patients harbor tumors that are resistant or relapse. Selective engagement of T-cell co-stimulatory molecules with bispecific antibodies may offer novel therapeutic options by enhancing signal 1–driven activation occurring via T-cell receptor engagement. In this study, we report the development and preclinical characterization of NI-3201, a PD-L1×CD28 bispecific antibody generated on the κλ-body platform that was designed to promote T-cell activity and antitumor function through a dual mechanism of action. We confirmed that NI-3201 blocks the PD-L1/PD-1 immune checkpoint pathway and conditionally provides T-cell co-stimulation via CD28 (signal 2) when engaging PD-L1+ tumors or immune cells. In systems with signal 1–primed T cells, NI-3201 enhanced potent effector functionality: in vitro through antigen-specific recall assays with cytomegalovirus-specific T cells and in vivo by inducing tumor regression and immunologic memory in tumor-associated antigen–expressing MC38 syngeneic mouse models. When T-cell engagers were used to provide synthetic signal 1, the combination with NI-3201 resulted in synergistic T cell–dependent cytotoxicity and potent antitumor activity in two humanized mouse tumor models. Nonhuman primate safety assessments showed favorable tolerability and pharmacokinetics at pharmacologically active doses. Quantitative systems pharmacology modeling predicted that NI-3201 exposure results in antitumor activity in patients, but this remains to be investigated. Overall, this study suggests that by combining PD-L1 blockade with safe and effective CD28 co-stimulation, NI-3201 has the potential to improve cancer immunotherapy outcomes, and the clinical development of NI-3201 for PD-L1+ solid tumors is planned. 

Journal: Cancer Prevention Research 

Ursolic Acid as a Protective Agent against UVB-Induced Metabolic and Epigenetic Alterations in Human Skin Keratinocytes: An Omics-Based Study 

This study aimed to assess how ursolic acid (UA) can protect human skin keratinocytes from damage caused by UVB radiation. Utilizing an omics-based approach, we characterized the features of photodamage and investigated the potential of UA to reverse HaCaT cell subpopulation injury caused by UVB radiation. The most significant changes in metabolite levels after UA treatment were in pathways associated with phosphatidylcholine biosynthesis and arginine and proline metabolism. Treatment with UA can reverse the levels of certain metabolites, including creatinine, creatine phosphate, and succinic acid. Pathways activated by UA treatment in UVB-irradiated HaCaT cells were associated with several biological processes, including the positive regulation of protein modification process, cell division, and enzyme-linked receptor protein signaling pathway. Treatment with UA demonstrates the capability to mitigate the effects of UVB radiation on specific genes, including S100 calcium-binding protein A9 and IL6 receptor. DNA/CpG methylation indicates that UA can partially reverse some of the alterations in the UVB-induced CpG methylome. Utilizing integrated RNA sequencing and methylation sequencing data, starburst plots illustrate the correlation between mRNA expression and CpG methylation status. UA potentially influences the metabolic pathway of glycerophospholipid metabolism by modulating the expression of several key enzymes, including phospholipase A2 group IIA and lipin 2. Altogether, these results indicate that UVB radiation induces metabolic reprogramming, epigenetic changes, and transcriptomic shifts. Meanwhile, UA demonstrates the capacity to inhibit or reduce the severity of these alterations, which may underlie its potential protective role against skin damage caused by UVB exposure. 

Prevention Relevance: Our research indicates that UA has the potential to mitigate or lessen the impact of UVB radiation, which is known to cause metabolic reprogramming, epigenetic alterations, and transcriptomic changes. These effects could be responsible for UA’s possible protective function against skin damage induced by UVB exposure. 

This story was featured on the cover of the March issue. 

Journal: Cancer Research (March 1 issue) 

Senescent Cell–Derived Extracellular Vesicles Inhibit Cancer Recurrence by Coordinating Immune Surveillance 

Senescence is a nonproliferative survival state that cancer cells can enter to escape therapy. In addition to soluble factors, senescence cells secrete extracellular vesicles (EV), which are important mediators of intercellular communication. To explore the role of senescent cell (SC)–derived EVs (senEV) in inflammatory responses to senescence, we developed an engraftment-based senescence model in wild-type mice and genetically blocked senEV release in vivo, without significantly affecting soluble mediators. SenEVs were both necessary and sufficient to trigger immune-mediated clearance of SCs, thereby suppressing tumor growth. In the absence of senEVs, the recruitment of MHC-II⁺ antigen-presenting cells (APC) to the senescence microenvironment was markedly impaired. Blocking senEV release redirected the primary target of SC signaling from APCs to neutrophils. Comprehensive transcriptional and proteomic analyses identified six ligands specific to senEVs, highlighting their role in promoting APC–T cell adhesion and synapse formation. APCs activated CCR2⁺CD4⁺ T_H17 cells, which seemed to inhibit B-cell activation, and CD4⁺ T cells were essential for preventing tumor recurrence. These findings suggest that senEVs complement the activity of secreted inflammatory mediators by recruiting and activating distinct immune cell subsets, thereby enhancing the efficient clearance of SCs. These conclusions may have implications not only for tumor recurrence but also for understanding senescence during de novo carcinogenesis. Consequently, this work could inform the development of early detection strategies for cancer based on the biology of cellular senescence. 

Significance: Chemotherapy-treated senescent tumor cells release extracellular vesicles that trigger an immune response and suppress tumor recurrence. 

A commentary related to the study was published in the March 1 issue. 

Journal: Cancer Research (March 15 issue) 

Evolutionary Pressures Shape Undifferentiated Pleomorphic Sarcoma Development and Radiotherapy Response 

Radiotherapy is an integral component in the treatment of many types of cancer, with approximately half of patients with cancer receiving radiotherapy. Systemic therapy applies pressure that can select for resistant tumor subpopulations, underscoring the importance of understanding how radiation impacts tumor evolution to improve treatment outcomes. We integrated temporal genomic profiling of 120 spatially distinct tumor regions from 20 patients with undifferentiated pleomorphic sarcomas (UPS), longitudinal circulating tumor DNA analysis, and evolutionary biology computational pipelines to study UPS evolution during tumorigenesis and in response to radiotherapy. Most unirradiated UPSs displayed initial linear evolution, followed by subsequent branching evolution with distinct mutational processes during early and late development. Metrics of genetic divergence between regions provided evidence of strong selection pressures during UPS development that further increased during radiotherapy. Subclone abundance changed after radiotherapy with subclone contraction tied to alterations in calcium signaling, and inhibiting calcium transporters radiosensitized sarcoma cells. Finally, circulating tumor DNA analysis accurately measured subclone abundance and enabled noninvasive monitoring of subclonal changes. These results demonstrate that radiation exerts selective pressures on UPSs and suggest that targeting radioresistant subclonal populations could improve outcomes after radiotherapy. 

Significance: Radiotherapy mediates tumor evolution by leading to the expansion of resistant subclonal cancer cell populations, indicating that developing approaches to target resistant subclones will be crucial to improve radiotherapy response. 

This article was featured on the cover of the March 15 issue. 

Journal: Clinical Cancer Research (March 1 issue) 

Phase II Pilot Trial of Tislelizumab plus Low-Dose Nab-Paclitaxel for Extensive Very High–Risk Non–Muscle-Invasive Bladder Cancer 

Purpose: Combinations of immune checkpoint inhibitors and nab-paclitaxel have improved outcomes in advanced urothelial carcinoma and muscle-invasive bladder cancer. This study evaluates the safety and efficacy of tislelizumab combined with low-dose nab-paclitaxel in extensive very high–risk non–muscle-invasive bladder cancer. 

Patients and Methods: TRUCE-02 was a single-arm phase II trial that included 63 patients with visually incomplete resection and/or high-volume high-grade T1 tumors (with or without carcinoma in situ) who were ineligible for or declined radical cystectomy. Patients received intravenous tislelizumab (200 mg on day 1) and nab-paclitaxel (200 mg on day 2) every 3 weeks, with assessment approximately 3 months after initial administration. The primary endpoint was the complete response (CR) rate of high-risk disease. Main secondary endpoints included safety and duration of CR. 

Results: The safety analysis included all 63 patients, and the efficacy analysis included 59 patients. Thirty-seven patients (62.7%; 95% confidence interval, 49.1%–75.0%) achieved a CR of high-risk disease, with a 24-month sustained response rate of 96.3% (95% confidence interval, 89.4%–100.0%). Grade 3 to 4 treatment-related adverse events occurred in nine patients (14%), with no fatal events reported. 

Conclusions: Tislelizumab plus low-dose nab-paclitaxel was well tolerated and showed promising antitumor activity, making it a potential alternative for patients with extensive very high–risk non–muscle-invasive bladder cancer who are ineligible for or decline radical cystectomy. 

Journal: Clinical Cancer Research (March 15 issue) 

Phase I Trial of TTI-101, a First-in-Class Oral Inhibitor of STAT3, in Patients with Advanced Solid Tumors 

Purpose: Signal transducer and activator of transcription 3 is a transcription factor that is essential for the survival and immune sequestration of cancer cells. We conducted a phase I study of TTI-101, a first-in-class, selective small-molecule inhibitor of signal transducer and activator of transcription 3, in patients with advanced metastatic cancer. 

Patients and Methods: Patients were treated with TTI-101 orally twice daily in 28-day cycles at four dose levels (DL): 3.2 (DL1), 6.4 (DL2), 12.8 (DL3), and 25.6 (DL4) mg/kg/day (“3+3” design). Three TTI-101 formulations were used in a stepwise manner (NCT03195699). 

Results: Sixty-four patients were treated (median age, 63 years; male sex, 52%; median number of prior therapies, 3). No dose-limiting toxicities or fatal treatment-related adverse events (TRAE) were observed. Diarrhea (mostly grade 1/2) was the only TRAE observed in ≥30% of subjects. Five patients experienced grade 3 TRAEs that resolved. TTI-101 showed linear pharmacokinetics from DL1 to DL3, with the pharmacokinetics plateauing at DL3. The recommended phase II dose is 12.8 mg/kg/day (DL3). Of the 41 patients who were evaluable for response, five (12%) had confirmed partial responses (cPR) and 17 (41%) had stable disease. Three (18%) of the 17 patients with hepatocellular carcinoma had a cPR (median time to treatment failure, 10.6 months). Two other cPRs were noted in one patient with ovarian cancer and one patient with gastric cancer. 

Conclusions: TTI-101 was well tolerated. cPRs were observed across tumor types. The antitumor activity of TTI-101 monotherapy in patients with advanced, metastatic solid tumors is promising. A phase II study of TTI-101 in hepatocellular carcinoma is currently underway. 

Journal: Molecular Cancer Research 

Stress and Obesity Signaling Converge on CREB Phosphorylation to Promote Pancreatic Cancer 

One of the deadliest types of cancer is pancreatic ductal adenocarcinoma (PDAC). Chronic stress and obesity are recognized as risk factors for PDAC. We hypothesized that the combination of stress and obesity strongly promotes pancreatic cancer development and growth. Here, we show that the stress mediator norepinephrine and the β-adrenergic receptor agonist isoproterenol rapidly stimulate cyclic adenosine monophosphate response element-binding protein (CREB) phosphorylation at Ser¹³³ in human PDAC cells. Exposure to the nonselective β-adrenergic receptor antagonist propranolol or selective antagonists, including nebivolol, atenolol, or ICI118551, blocked CREB phosphorylation elicited by norepinephrine or isoproterenol in PDAC cells. Stimulation of PDAC cells with neurotensin, a neuropeptide implicated in obesity and PDAC, also stimulated CREB phosphorylation at Ser¹³³. Mechanistically, norepinephrine induced CREB phosphorylation at Ser¹³³ via PKA, whereas neurotensin promoted CREB phosphorylation predominantly through protein kinase D. Our results indicate that CREB is a point of signal convergence that mediates proliferation in PDAC cells and raised the possibility that stress and diet cooperate in promoting PDAC in vivo. To test this notion, mice expressing KrasG12D in all pancreatic lineages (KC mice) and fed an obesogenic high fat, calorie diet that promotes early PDAC development were subjected to social isolation stress. We show that social isolation stress induced a significant increase in the proportion of advanced PDAC precursor lesions (pancreatic intraepithelial neoplasia) in KC mice subjected to an obesogenic high fat, calorie diet. 

Implications: Our data imply that chronic (social isolation) stress cooperates with diet-induced obesity in accelerating the development of pancreatic cancer. 

This article was highlighted in the March issue. 

Journal: Molecular Cancer Therapeutics 

A B7-H3–Targeted CD28 Bispecific Antibody Enhances the Activity of Anti–PD-1 and CD3 T-cell Engager Immunotherapies 

T-cell activation is a multistep process requiring T-cell receptor engagement by peptide–MHC complexes (Signal 1) coupled with CD28-mediated costimulation (Signal 2). Tumors typically lack expression of CD28 ligands, so tumor-specific Signal 1 (e.g., neoepitope presentation) without costimulation may be ineffective or even induce T-cell anergy. We designed the bispecific antibody XmAb808 to co-engage the tumor-associated antigen B7-H3 with CD28 to promote T-cell costimulation within the tumor microenvironment. XmAb808 costimulation was measured by its ability to activate and expand T cells and enhance T cell–mediated cancer cell killing in cocultures of human peripheral blood mononuclear cells and cancer cells and in mice engrafted with human peripheral blood mononuclear cells and tumor xenografts. XmAb808 avidly bound cancer cells and stimulated IL2 and IFNγ secretion from T cells cocultured with cancer cells engineered to deliver Signal 1 to T cells via a surface-expressed anti-CD3 antibody. XmAb808 enhanced expression of the antiapoptotic factor Bcl-xL and CD25, promoting survival and IL2-dependent expansion of T cells coupled with increased T cell–mediated cytotoxicity in vitro. XmAb808 combined with an EpCAM×CD3 bispecific antibody to enhance target cell killing through IL2-dependent expansion of CD25+ T cells. This combination also suppressed pancreatic tumor xenograft growth in mice. Furthermore, XmAb808 combined with an anti–programmed cell death protein 1 antibody to suppress breast tumor xenograft growth in mice. XmAb808 as monotherapy and in combination with an anti–programmed cell death protein 1 antibody is currently in clinical development in patients with advanced solid tumors. Our results suggest that XmAb808 may also combine with tumor antigen–targeted anti-CD3 (Signal 1) T-cell engagers. 

This article was highlighted in the March issue. 

Journal: Cancer Research Communications 

Variant of Uncertain Significance Patterns among Patients with Early-Onset Colorectal Cancer 

The increasing burden of colorectal cancer among adults younger than age 50 years (early-onset colorectal cancer) and new National Comprehensive Cancer Network guidelines recommending universal genetic testing in early-onset colorectal cancer emphasize the need for accurate and timely variant classification in clinical care. In this study, we investigated germline variant of uncertain significance (VUS) patterns among diverse individuals with early-onset colorectal cancer. A total of 3,980 individuals ages 15 to 49 years when diagnosed with a first primary colorectal cancer, including 1,001 cases identifying as non-White, who underwent genetic testing for 14 colorectal cancer susceptibility genes performed by a clinical testing laboratory were included. A five-tier classification system was applied to all alterations to classify VUSs and was updated in March 2024. Disparities in variant reclassification rates emerged by self-identified race/ethnicity (P < 0.0001). A total of 4.8% of Ashkenazi Jewish, 18.2% of Asian, 12.2% of Black, 7.6% of Hispanic, and 6.7% of White individuals had at least one reclassified VUS. After reclassification, 356 individuals (8.9%) presented with 1+ VUSs. VUSs significantly varied by self-identified race/ethnicity (P = 0.008). Young individuals identifying as Black and Hispanic had significantly higher odds of presenting with a VUS compared with those identifying as White in multivariable logistic regression models. Individuals who identified as Black and Asian were significantly more likely to present with a VUS in PMS2 (OR = 3.59; 95% confidence interval, 1.73–7.48; P = 0.0006) and MSH2 (OR = 3.14; 95% confidence interval, 1.17–8.45; P = 0.02), respectively, compared with those identifying as White. These findings define unique VUS patterns in early-onset colorectal cancer by race and ethnicity, pointing to distinct germline variant spectra and to the potential for the discovery of novel ancestry-specific variants associated with early-onset colorectal cancer that will guide efforts to reduce clinical uncertainty and improve equitable care. 

Significance: Among individuals with early-onset colorectal cancer, germline VUS reclassification as well as rates of VUSs in cancer susceptibility genes differed by self-identified race/ethnicity. These findings point to the importance of VUS reclassification as this may alter clinical management and to distinct germline variant spectra among diverse patients with early-onset colorectal cancer. 

Breakthroughs in kidney cancer research, including new insights into the tumor-immune microenvironment and the identification of metabolic vulnerabilities, are reshaping the future of treatment, creating opportunities for therapies tailored specifically to individual patients. These cutting-edge developments in personalized vaccines targeting tumor-specific mutations, novel cell therapies, and biomarkers that can predict treatment responses, could help to revolutionize kidney cancer care and significantly enhance patient outcomes and quality of life.

Personalized Neoantigen Vaccines: A Potential Leap Forward for Kidney Cancer

At the forefront is a remarkable personalized neoantigen vaccine approach that targets mutated protein fragments known as neoantigens that are expressed exclusively by cancer cells. This strategy has been effective for immunogenic tumors like melanoma and lung cancers that often carry many mutations, but until now, had yet to show much promise in cancers that typically harbor fewer mutations, including kidney cancer.

In a recent phase I trial, nine patients with advanced clear cell renal cell carcinoma (ccRCC) received peptide-based vaccines tailored to their tumors’ specific mutations after their tumors were fully resected. Renal cell carcinoma is the most common form of kidney cancer, accounting for approximately 90% of kidney cancer cases, and the clear cell subtype accounts for roughly 80% of RCC cases.

Of the nine patients in the trial, five of whom were also treated with the immune checkpoint inhibitor (ICI) ipilimumab (Yervoy), none experienced disease relapse at a median follow-up of 40.2 months. Eight of the nine patients have had at least two years of follow-up, and the ninth unfortunately died from an unrelated cause, after no evidence of disease was observed at their final, 19-month follow-up. Impressively, five of these patients have gone more than three years without recurrence. Additionally, the vaccines successfully induced durable T-cell responses, predominantly from memory CD4-positive cells that had already encountered antigen.

One aspect of this promising approach involved targeting driver mutations, genetic alterations that play a central role in enabling tumor growth and survival. A prime example in kidney cancer is the tumor suppressor gene VHL. Mutations that inactivate VHL and prevent it from fulfilling its tumor suppressor duties are a hallmark of ccRCC, through their impact on pathways crucial for tumor development. But mutant VHL-derived peptides can also provide targets for the immune system, as demonstrated by a pioneering 2010 pilot study in which a peptide vaccine elicited immune responses against mutant VHL in four of the five patients treated. Building upon this foundation, the recent personalized neoantigen vaccine strategy incorporated mutate VHL in addition to several other mutant driver targets that the patients’ kidney cancers harbored.

Cell Therapy and the Solid Tumor Microenvironment

Besides personalized vaccines, cell therapies have gained some traction in treating kidney cancer. One example is an innovative CAR T-cell therapy targeting the CD70 receptor. Unlike currently approved CAR T-cell therapies, which are created from patients’ own harvested immune cells, this CD70 CAR T-cell therapy is created using healthy donor T cells, offering a more readily available and predefined cell therapy product. Additionally, in contrast to neoantigens that are unique to individual tumors, CD70 is a tumor-associated antigen linked to immunosuppression and frequently overexpressed in ccRCC.

In a phase I study, the CD70-targeting therapy, CTX130, prevented disease progression in 13 of 16 patients with advanced ccRCC. Most patients experienced disease stabilization, and one patient experienced complete elimination of their tumor and remained disease-free three years later, underscoring the potential of engineered cell therapies.

The development of superior therapies will require navigating the complex and uniquely challenging tumor microenvironment of kidney cancers. Recent research underscores kidney tumors’ extensive extracellular matrix remodeling and unusually high interstitial fluid pressure, which can create a physical barrier that limits the distribution of drug delivery within tumors and promotes resistance. Understanding and targeting these aspects of tumors could significantly improve the effectiveness of current and future therapies.

Metabolic Vulnerabilities as Therapeutic Targets

Metabolism has also emerged as a critical factor in kidney cancer biology, revealing numerous potential therapeutic targets. For instance, researchers discovered that ccRCC cells exploit a mitochondrial enzyme, MTHFD2, to enhance glycosylation of the growth-promoting protein c-MYC and thereby drive resistance to the commonly used targeted therapy sunitinib (Sutent). Blocking MTHFD2, therefore, could restore drug sensitivity.

Another study showed that ccRCC tumors accumulate copper, which fuels mitochondrial energy production and tumor growth. Interrupting copper metabolism could weaken tumor cells, opening another avenue for therapeutic intervention.

Lipid metabolism is another critical axis of ccRCC survival. ccRCC tumors depend on elevated lipid uptake and storage, which provide essential energy reserves and structural components that help tumor cells endure cellular stress. In particular, metastatic ccRCC cells manipulate lipid-related receptors such as GPR1 and CMKLR1 to enhance lipid accumulation, bolstering their ability to resist stress-induced death.

Within these lipid stores, cholesterol is the most abundant component, playing a central role in maintaining cellular homeostasis. To manage this dependency, ccRCC tumors rely on enzymes like HSD3B7, which regulate cholesterol and bile acid metabolism to prevent the buildup of toxic cholesterol metabolites. Targeting this lipid network, both at the receptor level and within downstream metabolic pathways, represents a promising therapeutic strategy that could disrupt tumor survival mechanisms and trigger cancer cell death.

Likewise, modulating tryptophan metabolism by inhibiting the enzyme PABPC1L could enhance immune responses by preventing immune suppression, further boosting the effectiveness of immunotherapies.

Biomarkers: Paving the Path to Precision Medicine

As treatments become more specialized and complex, biomarkers will be crucial for pairing patients with the right treatments and predicting therapy responses. To that end, scientists identified immune cell signatures, such as certain subpopulations of natural killer cells and regulatory T cells in the blood of metastatic kidney cancer patients, that could serve as predictors of response to immune checkpoint blockade. Meanwhile, CA-125 has emerged as a promising noninvasive biomarker in renal medullary carcinoma, a rare and aggressive kidney cancer linked to sickle cell trait, correlating with metastatic burden and disease progression

Collectively, these developments—from personalized neoantigen vaccines and CAR T therapies to deepened understanding of the tumor-immune microenvironment and metabolic vulnerabilities—signal a convergence towards precision-driven kidney cancer care. The insights gained position researchers and clinicians to pursue treatments offering genuine leaps forward in survival and quality of life for kidney cancer patients.

After Craig Schumpert learned he had lung cancer that had spread to his brain, bones, and lymph nodes, he started radiation therapy. His oncologist told him he might be eligible for targeted therapy, but he would have to wait four to six weeks for results from tumor tissue testing. The possibility of targeted therapy sounded promising, but the wait did not. “When you get diagnosed with cancer, it’s like, get me on some kind of treatment,” Schumpert says. But his doctor also ordered a liquid biopsy test that could detect traces of cancer in his blood. Those results came back just a week later, revealing a fusion in the ALK gene. Schumpert started taking an ALK inhibitor, and within weeks, the tumor began to shrink. 

While tumor tissue testing remains the gold standard for guiding cancer treatment choices, Schumpert’s story illustrates how liquid biopsies can provide information about cancer in less time. In the feature story, which appears in Cancer Today, a magazine and online resource for cancer patients, survivors, and caregivers published by the American Association for Cancer Research (AACR), oncologists describe how they use liquid biopsies to care for patients with many types of cancer, and what people with cancer should know. 

Another story in the spring issue details how people with metastatic hormone receptor-positive breast cancer are living longer with the disease, thanks to a growing number of treatment options. Although metastatic hormone receptor-positive breast cancer remains incurable, new targeted treatments and endocrine therapies can help keep the cancer in check. “Even if we can’t cure the disease, the promise is we’ll be able to switch from one treatment approach to another and have a series of therapies that may be helpful to extend life and hopefully maintain quality of life,” William Gradishar, MD, a medical oncologist at the Robert H. Lurie Comprehensive Cancer Center in Chicago, says in Cancer Today. 

In the same issue, Cancer Today explores the challenges that come with receiving cancer treatment in rural areas. An estimated 20% of the American population resides in rural areas, but just 3.1% of medical oncologists and hematologists practice there. These patients often face significant barriers to receiving care, including long travel times and limited access to specialists and clinical trials.  

People with cancer also face the challenge of finding adequate mental health support. A profile of hospital psychologist Ethan Schilling describes his experiences as a childhood cancer survivor and how his mother helped to support him and his twin brother, Derek, after they were both diagnosed with the same rare brain tumor at different ages. Today, Schilling focuses on approaches that help children and young adults identify healthy strategies for coping with their new reality. “Cancer and brain tumors are a big part of my identity, and I see it as part of my role and passion to advocate and do what I can to make things better for these folks and their families,” Schilling says. 

Cancer Today’s latest issue also highlights practical information for patients, including analysis of a study on an experimental treatment for cancer cachexia. Stories also offer advice on topics ranging from dealing with treatment-related changes to taste and smell to the power of mindful breathing in alleviating cancer-related pain and anxiety. Plus, William G. Nelson, MD, PhD, director of the Johns Hopkins Kimmel Cancer Center in Baltimore and Cancer Today’s editor-in-chief, provides commentary about the promise of FLASH radiation, which delivers high doses of radiation in just milliseconds to reduce damage to normal tissue while still killing cancer cells. 

The AACR offers Cancer Today free of charge to those affected by cancer. To view content from the spring issue, visit Cancer Today’s website or read the digital edition.  

To stay up to date with the latest in cancer research and care, subscribe to the magazine or sign up to receive Cancer Today’s e-newsletter released twice a month. 

If Eddie and Alex Van Halen hadn’t asked David Lee Roth to join their band so they wouldn’t have to keep renting his PA system, would we have Van Halen? If Larry Mullen, Jr., never posted a note on his high school bulletin board looking for band members, would he have ever met Paul Hewson (Bono), David Evans (The Edge), and Adam Clayton and formed U2? If Roger Waters and Nick Mason weren’t both studying architecture in London, would we have Pink Floyd? And if it wasn’t for one very long escalator ride at a medical conference in Chicago, would we have The CheckPoints? 

The CheckPoints may not have the same name recognition as those other bands, but they are well-known among cancer researchers—both for their contributions to the field of immuno-oncology and their ability to bring the house down at any conference where they perform. That includes the AACR Annual Meeting 2024 where they had the audience singing “We Are the Champions” and “Don’t Stop Believin’.” They are ready to once again rock this year’s AACR Annual Meeting during the Annual Reception on Sunday, April 27, in Chicago—the city where it all began for them.  

In 2007, Patrick Hwu, MD, Rachel Humphrey, MD, and Thomas F. Gajewski, MD, PhD, had just wrapped up a sparsely attended series of lectures on immuno-oncology—this was back when the idea still had its doubters. It was the final day of the conference and the three of them were headed out. While embarking on an escalator ride long enough to “eat a tuna sandwich,” as Humphrey described it, Hwu mentioned he wanted to start a blues band, similar to the bands he had played in as a resident at Johns Hopkins and then a researcher at the National Institutes of Health (NIH). Gajewski played the guitar, so he was in. Humphrey chimed in that she could sing. By the time they reached the bottom, they had a solid plan. A couple of hours later, they recruited James P. Allison, PhD, FAACR, to play the harmonica.  

After a few performances, Allison suggested they call themselves The CheckPoints—a nod to their contributions to the first immune checkpoint inhibitor, ipilimumab. Allison was the researcher who discovered the function of CTLA-4 and how it could act as a brake on T cells and developed ipilimumab to block it, a discovery for which he received the 2018 Nobel Prize in Physiology or Medicine. Humphrey was the senior supervisor of the global development for ipilimumab at Bristol Myers Squibb. And Gajewski and Hwu were clinician-scientists who were treating patients with ipilimumab, while making their own strides in immuno-oncology.  

Over the years, the band added percussionists, a horn section, additional vocalists, a bass player, and more. Now, The CheckPoints has over a dozen members who are all cancer researchers, medical oncologists, or other professionals in the field of immuno-oncology. Before you enjoy their performance at the AACR Annual Meeting 2025, here’s an opportunity to learn a little about their work, their love of music, and what songs they can’t wait to play in Chicago.

Ladies and gentlemen, meet The CheckPoints. 

Patrick Hwu, MD  

President and CEO, Moffitt Cancer Center 

Instrument: Keyboard  

His Work: “In my role as CEO of Moffitt Cancer Center, I’m inspired by our patients, team members, and community all being focused on our mission to help cancer patients and discover better ways to prevent and cure tomorrow’s patients,” Hwu said. “I am most excited about the advances we continue to make in T-cell therapy and tumor immunology. We are starting to see good responses in patients with solid tumors and I’m looking forward to continued progress. We know so much today about the science of tumor biology and immunology that now is the time as a society that we need to put the pedal to the metal to urgently save more lives.” 

Favorite Musical Memory: “I love playing with The CheckPoints, especially for the enthusiastic, energetic dancing crowd that often joins us!” 

Favorite Song to Perform: “Journey’s ‘Don’t Stop Believin,’ not only because it has a great piano part, but because it represents the many years we worked as immunologists with the belief that our approach would one day help patients, as we all now know today.  Also, it’s a song of inspiration for cancer patients, since there is so much research and new treatments coming along every day.” 

Thomas F. Gajewski, MD, PhD 

AbbVie Foundation Professor of Pathology; Professor of Ben May Department of Cancer Research; Professor of Medicine; Committee on Cancer Biology; Committee on Clinical Pharmacology and Pharmacogenomics, University of Chicago 

Instrument: Guitar 

His Work: “We have been working on gaining a more detailed understanding of the mechanisms of resistance to checkpoint blockade therapy,” Gajewski explained. “Through this translational research approach, we’ve identified new immune regulatory molecules, some of which are targetable with antibodies and others with small molecule inhibitors. In addition, we have worked out some detailed mechanisms of how the gut microbiota regulates antitumor immunity and have built infrastructure for getting microbiome-based interventions into patients.” 

Favorite Musical Memory: “A highlight was the first time we played with Buddy Guy himself, during an ASCO/SITC party. I was playing guitar between a Nobel Prize-winning harmonica player and a Grammy Award-winning blues singer!” 

Favorite Song to Perform: “Having just seen the new Led Zeppelin movie, I’m reminded how important their music was to my musical formation. I would work for hours learning Jimmy Page guitar solos from vinyl records. We play one of their songs, ‘Rock and Roll,’ and I love playing that solo!” 

Rachel Humphrey, MD 

President and Founding CEO, Normunity 

Instrument: Lead vocals 

Her Work: “I’m the CEO of a Boston-based biotech that’s moving a new medicine, NRM-823, into early phase I testing in patients this coming fall,” Humphrey said. “The drug is a T-cell engager, based on science out of Lieping Chen’s lab at Yale. The data we’ve seen thus far in animal models suggests that NRM-823 has the potential to help the lives of patients with a wide variety of cancer types.” 

Favorite Musical Memory: “I love singing with The CheckPoints! We’ve been doing it since 2007, and every year it gets better. There’s nothing like making music for a lot of dancing, happy people!” 

Favorite Song to Perform: “By the time we play Nivana’s ‘Teen Spirit,’ the dance floor is usually hopping wildly, and everyone is jumping up and down. Last year, it felt like the floor was bouncing, even on the edges of the room! Also, there’s nothing like The Beatles’ ‘Let It Be’ at the very end, when everyone has their phone flashlights on, and the people who join us on the stage are wrapped around each other, swaying to the rhythm.” 

James P. Allison, MD, FAACR 

Regental Professor and Chair of the Department of Immunology; The Olga Keith Wiess Distinguished University Chair for Cancer Research; Director of the Parker Institute for Cancer Research; Executive Director of the Immunotherapy Platform; Director of the James P. Allison Institute, MD Anderson Cancer Center 

Instrument: Harmonica 

His Work: Allison is currently focused on finding new approaches and new targets for immunotherapy. “We’re getting there,” Allison said at AACR IO 2025, “but we know we can do better.” For example, he suggested moving away from drug development strategies that focus on single-agent activity. He pointed to long-term clinical data showing that of the patients treated with ipilimumab plus nivolumab (Opdivo), who were recurrence-free at the three-year mark, 96% lived at least 10 years after treatment. He is also working on studies trying to define a feedback loop between T cells and macrophages within tumors in order to better understand the tumor microenvironment. 

Favorite Musical Memory:  A long-time fan of Willie Nelson, Allison has had the opportunity to play with him on multiple occasions. The first time came when he was in his 20s and working as a postdoc in San Diego and ended up at the same party as Nelson and his bass player. Allison fell into a conversation with them and took them to a club where they could play music, and they let him sit in on one song. The next time came after winning the Nobel Prize when Mickey Raphael, the harmonica player in Nelson’s band, read an interview where Allison stated his fondness for Nelson and invited him to play with the musical icon. Since then, Allison has shared the stage with Nelson a few other times, including at the Austin City Limits Festival in front of 70,000 people.  

Favorite Song to Perform: In addition to his Nelson fandom, Allison’s affinity for The Doors helped make Wolchok a fan of ‘Roadhouse Blues’ (learn more below).  

John M. Timmerman, MD 

Professor of Medicine, UCLA Lymphoma Program; Division of Hematology and Oncology, Department of Medicine, David Geffen School of Medicine at UCLA 

Instrument: Guitar  

His Work: “My areas of research include advances being made in the biology and immunotherapy of B cell malignancies,” Timmerman said. “We are making progress understanding the immune factors that govern responses to CAR T cells and bispecific antibodies, and how these might be manipulated to increase cure rates.” 

Favorite Musical Memory: “Playing live with The CheckPoints! We love sharing our music with the great crowd at the AACR Annual Meeting. The best part is bringing new songs to our audience, and surprising them, as we will in Chicago this April!” 

Favorite Song to Perform: “We always love doing ‘Sweet Home Chicago,’ since it includes every single member of the band, and all the instruments take a solo, so it’s a highlight of the night! And I love when our three singers are harmonizing, like on ‘The Chain’ by Fleetwood Mac and ‘Take It Easy’ from the Eagles, among others.” 

Brad Reinfeld, MD, PhD 

Incoming Memorial Sloan Kettering Clinical Oncology Fellow 

Instrument: Bass 

His Work: “I am in the full-time clinical stage of my training,” Reinfeld said. “However, based on my experience taking care of patients on novel weight loss therapies (GLP-1a family), I am excited to see what these medications can potentially do for the prevention of cancer. Additionally, these drugs offer hope that understanding the molecular mechanisms of metabolism can result in profound clinical improvements!” 

Favorite Musical Memory: “I saw Stevie Wonder on my first day of high school with my mom at the Greek Theater in Los Angeles. My favorite artist at my favorite venue!” 

Favorite Song to Perform: “With The CheckPoints, it has to be ‘Sweet Home Chicago!’ How often do you see a Nobel Prize winner, cancer center directors, a biotech CEO, and a medical student all solo on the same song!” 

Rob Jankowski, PharmD 

Executive Director, Hematology/Oncology, Medical Affairs, Legend Biotech 

Instrument: Drums 

His Work: “Our research focus is on cellular therapy for hematologic malignancies and solid tumors,” Jankowski explained. “While many of our pipeline assets are autologous CAR T therapies, I am particularly interested in our allogeneic therapies for hematologic malignancies as well as our autologous therapies for solid tumors for which there is tremendous unmet medical need.” 

Favorite Musical Memory: “When I shared the stage with Jim Allison, a Nobel laureate, and Buddy Guy, the legendary blues icon. I have never backed such prestigious people like that. Truly an honor!” 

Favorite Song to Perform: “Toto’s ‘Rosanna’ is particularly challenging and fun to play on the drums.” 

Jedd D. Wolchok, MD, PhD, FAACR 

Meyer Director, Sandra and Edward Meyer Cancer Center; Professor of Medicine, NewYork-Presbyterian/Weill Cornell Medical Center 

Instrument: Tuba 

His Work: “As a cancer center director, my major efforts are taking care of patients, but I also continue to run my laboratory, which explores new ways to use the immune system to control cancer,” Wolchok explained. “We are looking at new cell therapies, such as CAR T cells for solid tumors, as well as agonist pathways that will cause the immune system to respond more vigorously to cancer.” 

Favorite Musical Memory: “I also play classically in a wind ensemble in New York City, and we’ve had the great privilege of performing on stage in Carnegie Hall. Another highlight was my wedding because my wife, who is a music therapist, and I performed together. She has also joined The CheckPoints on occasion and will be playing percussion at this year’s Annual Meeting.” 

[Editor’s Note: Get ready to shout, “more cowbell,” because one of the instruments she will be playing is in fact the cowbell, along with the congas, but we all know which of those legendary music producer Bruce Dickinson needs a prescription for.]   

Favorite Song to Perform: “I really love U2’s ‘Angel of Harlem,’ because it has a beautiful part for the horn. I also now enjoy ‘Roadhouse Blues,’ because my first time playing with The CheckPoints it was just me, Jim Allison, and a couple of other people, and he wanted to play a Doors’ song. Since the song doesn’t have a part for the tuba, I just said, ‘Tell me the key,’ and started honking away on ‘Roadhouse Blues’ and it has become a real favorite.” 

Ferran Prat, PhD, JD 

Senior Vice President, Research Administration and Industry Relations, MD Anderson Cancer Center 

Instrument: Saxophone 

His Work: “I’m not directly conducting research (I’m not smart enough for that),” Prat joked, “but what excites me is making other people’s groundbreaking science possible. My team’s role at MD Anderson is to secure strategic funding, build alliances, and ensure that researchers have the resources they need to make a real impact. To put it in Hollywood terms: The researchers are the rockstars, and my team and I are their agents.” 

Favorite Musical Memory: “Without a shadow of a doubt, the feeling of uncertainty of whether the 5th floor of the Marriott Hotel in Boston would crack and break down, as almost a thousand people were pogoing at the rhythm of ‘Smells Like Teen Spirit.’ I don’t think the architects of the building had planned for that specific contingency.” 

Favorite Song to Perform: “Give me a solid funk groove, and you’ll immediately see a smile on my face. But in terms of songs that I perform with The CheckPoints, ‘25 or 6 to 4’ by Chicago has got to be my favorite. It has amazing horn arrangements, and as a bonus, we get to hear Tom Gajewski killing it on the (very difficult) guitar solo. It’s an honor being next to him as he makes his guitar literally scream.” 

Jason J. Luke, MD 

Associate Director for Clinical Research; Director, Immunotherapy and Drug Development Center; Associate Professor of Medicine, UPMC Hillman Cancer Center and University of Pittsburgh 

Instrument: Trumpet 

His Work: “I am very excited about synthetic biology approaches for cancer such as programable RNAs,” Luke said. “These approaches have the potential to expand the range of therapeutic targets available and broaden the therapeutic window we can explore. As an example, we are working on a lipid-nanoparticle delivered mRNA IL12 (STX-001) that appears extremely promising early in clinical development.” 

Favorite Musical Memory: “Playing the SITC party the year Jim won the Nobel Prize. The atmosphere of the crowd was amazing and something I have never experienced before. Nobody was there to see me, of course, and I’m just thankful to have participated.” 

Favorite Song to Perform: “My favorite CheckPoints tune that we play is ‘The Letter’ from Joe Cocker. Great horn parts and the band really rocks.” 

Russell Pachynski, MD 

Associate Professor, Director of Genitourinary Oncology Research, Division of Oncology, Washington University School of Medicine 

Instrument: Trombone 

His Work: “I recently patented a novel immunotherapy that could potentially treat multiple tumor types, and based on this, I founded a company called Pixie Bio,” Pachynski said. “We have a platform approach in solid tumors, with our lead in prostate cancer. It’s a new experience for me, but it’s so great to be able to play awesome music with some leaders in the field who have already done this. I feel fortunate to play music with people who are not only my friends and colleagues, but mentors and inspirational leaders in academia and industry!” 

Favorite Musical Memory: “Every CheckPoints show is super exciting but seeing Radiohead in Berlin during Oktoberfest in an open-air amphitheater, then heading to Oktoberfest tents after is hard to beat!” 

Favorite Song to Perform: “Chicago’s ‘25 or 6 to 4.’ It has rippin’ horns and crazy guitar, is upbeat, and when we play it in Chicago, the crowd goes wild!” 

Lisa Butterfield, PhD 

Distinguished Scientist, Discovery Oncology, Merck 

Instrument: Vocals 

Her Work: “At Merck, I’m focused on solid tumor immuno-oncology in general and the Merck-Moderna collaboration on individualized neoantigen therapies, specifically,” Butterfield explained. “There are enormous opportunities to reduce tumor recurrence rates with RNA/lipid nanoparticles encoding patient-specific antigens—it’s impossible not be excited about what is now technologically possible and in multiple phase II/III trials being tested in early-stage disease.” 

Favorite Musical Memory: “Early on it was singing in a madrigal group at a Bach festival in Los Angeles in junior high. We were the ‘echo’ for the Los Angeles Master Chorale for a performance in Russian at the Dorothy Chandler Pavilion.”  

Favorite Song to Perform: “Right now, it’s ‘The Chain’ by Fleetwood Mac. I really enjoy the harmonies.” 

Anna M. Crosetti, MD 

Intern (Soon to be Resident), Massachusetts General Hospital for Internal Medicine 

Instrument: Vocals 

Her Work: “I spent many years in the immunotherapy space before becoming a doctor, running research clinical trials and watching the rapid evolution of the field, starting with the checkpoint inhibitors and ending with the engineered cell therapies,” Crosetti explained. “It inspired me to become a doctor and oncologist, and I’m now finding my research identity in the single-cell RNA sequencing space, dissecting the tumor microenvironment and immunologic responses to therapies.” 

Favorite Musical Memory: “My first time meeting the band was at a Cancer Research Institute gala. I was invited at the very last minute and scrambled to find a dress for the formal event. I ended the night at 4 a.m., sitting in a hotel suite with all the band members, singing every lyric to ‘American Pie’ by heart.” 

Favorite Song to Perform: “I love harmonizing on ‘All About That Bass’ with Rachel and feeding off each other’s energy on stage. We have so much fun with the song.” 

Cancer screenings are key to saving lives. Take colonoscopies, for example, which are estimated to reduce colorectal cancer risk by about 30%. This is because undergoing colonoscopies as recommended (every 10 years beginning at age 45 for those at average risk) gives physicians the chance to detect and remove precancerous growths called adenomas (a type of polyp) before they can turn into colorectal cancer. 

But individuals with a history of adenomas continue to have an increased risk of colorectal cancer, even after they’re removed, in part because the removed adenomas often return. Researchers, therefore, are looking for additional ways to intercept colorectal cancer—in other words, stop precancerous cells in their tracks before they become cancerous. 

One approach is to use vaccination to train the patient’s immune system to recognize and respond to cellular changes associated with cancer. Research from Olivera Finn, PhD, a distinguished professor of immunology and surgery at the University of Pittsburgh, suggests that a vaccine that triggers immune responses to a protein called MUC1 could be a promising strategy to prevent colorectal cancer. 

MUC1 is found on the surface of cells lining the colon and rectum and is responsible for producing mucus and activating certain cellular signaling pathways. While it is found on healthy (noncancerous), precancerous, and cancerous cells, the sugar molecules bound to MUC1 adopt a unique pattern in precancerous and cancerous cells. To spare healthy cells, the experimental vaccine developed by Finn and colleagues trains immune cells to recognize MUC1 proteins with the precancer- and cancer-associated sugar patterns, allowing them to eradicate these cells before they can form either a precancerous adenoma or a cancerous tumor. 

In 2013, Finn and colleagues reported in the American Association for Cancer Research (AACR) journal Cancer Prevention Research that their experimental MUC1-targeted vaccine was safe and induced long-lasting MUC1-specific immune responses in 17 of 39 vaccinated patients who had a history of advanced adenomas and who received the vaccine as part of a phase I/II clinical trial. For the 22 patients who did not develop a response to the vaccine, immune analyses suggested that preexisting immune-suppressing cells may have hindered the vaccine’s effectiveness. 

Reducing the Risk of Polyp Recurrence 

Based on these results, Finn and colleagues tested the ability of their vaccine to prevent adenoma recurrence in a phase III clinical trial. As reported in 2023 in the AACR journal Clinical Cancer Research, of the 11 patients who developed vaccine-induced immune responses, eight benefited from it, while three (27%) had an adenoma recurrence. In comparison, 31 of 47 (66%) patients who received a placebo treatment had adenoma recurrence. This represents a 38% absolute reduction in risk of redeveloping these polyps with vaccination. The reduction was not statistically significant, but the researchers suggested that adjustments to the timing of vaccination and strategies to counter immune-suppressing cells around the target cells could improve the vaccine’s efficacy. In addition to colorectal cancer, the vaccine is also being tested to prevent breast cancer. 

Future studies to develop interception strategies for colorectal cancer will benefit from a deeper understanding of how normal tissue evolves to precancer and cancer. In three recent publications, researchers reported new insights into colorectal cancer development. The studies are a part of a collection published in Nature journals by the Human Tumor Atlas Network, a Cancer Moonshot initiative supported by the National Cancer Institute that is using cutting-edge tools to understand the molecular changes that occur as cancer forms.  

In the studies focused on colorectal cancer, researchers identified that changes to the regulation of gene expression, protein-protein interactions, cellular metabolism, hormone levels, immune responses, and other processes are associated with the formation of precancerous adenomas and cancerous tumors. They also found that as colorectal cancer cells spread to other parts of the body, they start to lose the features characteristic of colorectal cells and become increasingly like stem cells that do not have a particular identity. These studies provide new resources and insights for researchers that could help them uncover novel targets and strategies for colorectal cancer detection and interception. 

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Researchers continue to develop new strategies to detect and intercept cancer. Learn more about ongoing efforts in an AACR interview with leading cancer researchers.

“The story of effective cancer immunotherapies starts with the understanding of the function of CTLA-4, which was elucidated 30 years ago by the groups of James Allison and Arlene Sharpe,” declared Antoni Ribas, MD, PhD, FAACR, scientific committee chair of the inaugural AACR IO conference and AACR Past President 2020-21, as he introduced the opening keynote session celebrating the history of immune checkpoints. 

The meeting, whose theme is “Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy,” is being held February 23-26, 2025 in Los Angeles. 

It’s been three decades since seminal discoveries lit the fuse of cancer immunotherapy, transforming oncology and cementing immunotherapy’s place in cancer care. The revelation of the powerful roles played by immune checkpoints sparked a paradigm shift. No longer were doctors limited to targeting tumors directly. Now, they could help patients by enabling their immune system to do what it does best: protect us from threats.  

Igniting Cancer Immunotherapy 

In the first step on his path to the 2018 Nobel Prize in Physiology or Medicine, James P. Allison, PhD, FAACR, now the Regental Professor and chair of the Department of Immunology and director of the James P. Allison Institute at The University of Texas MD Anderson Cancer Center, demonstrated that antibodies against CTLA-4 could eliminate tumors in mice—proof that the immune system could be reprogrammed to fight cancer. The same year, Arlene H. Sharpe, MD, PhD, FAACR, now the Kolokotrones University Professor at Harvard University and chair of the Department of Immunology at Harvard Medical School, created mice that lacked CTLA-4, which revealed that CTLA-4 acts as a brake on T cells and confirmed its role as an immune checkpoint of consequence. 

Sharpe and Allison were just getting started, but few in 1995 could have foreseen where their work would lead. Or the impact it would make in patients’ lives. 

In particular, Allison told the story of his relationship with Sharon Belvin, whom he first met after his anti-CTLA-4 therapy cured her seemingly incurable metastatic melanoma. “Doctors couldn’t find any tumors in any of her scans, anywhere, and at first they thought they’d mixed them up,” Allison recounted. 

“I got to know her pretty well, to the point that she asked me to officiate her marriage years later. She also came with us to Stockholm for the Nobel Prize,” Allison beamed. “More importantly, she’s still doing fine today, 20 years out, with no subsequent retreatment.” 

During their keynote lectures, Allison and Sharpe shared the trailblazing journey of developing checkpoint immunotherapy. They reflected on how a once-radical idea evolved into a pillar of cancer care. From the initial discoveries to the widespread clinical success of checkpoint inhibitors, they highlighted the scientific milestones that expanded immunotherapy’s reach across multiple cancer types and hinted at how we might foster the next generation of breakthroughs. 

Their pioneering work on CTLA-4, which led to the FDA approval of ipilimumab (Yervoy) in 2011, also opened the door for the next immune checkpoint target: PD-1. In 2014, the first PD-1 checkpoint inhibitors received FDA approval, and they now form the backbone of modern cancer immunotherapy. 

Recent Advances and New Frontiers 

Turning back to the present, Allison shared insights from recent studies exploring the complexities of the tumor microenvironment, including defining a feedback loop between T cells and macrophages within tumors. He also highlighted long-term clinical data demonstrating the durability of dual checkpoint blockade responses, finding that nearly half of metastatic melanoma patients treated with ipilimumab plus nivolumab (Opdivo) survived at least six years. Impressively, 96% of the patients who were recurrence-free at the three-year mark lived at least 10 years after treatment.

Despite immunotherapy’s successes, Allison emphasized the need for a broader approach in identifying new immune checkpoints to target therapeutically, urging the field to rethink drug development strategies that overemphasize single-agent activity. 

In search of new cures, Sharpe has delved into the microbiome and its ability to shape patient responses to immunotherapy. While it’s long been understood that gut bacteria influence treatment outcomes, Sharpe sought to learn more about how this happens. “I hoped that we could get a better mechanistic understanding of how so called ‘good’ bacteria work to enhance cancer immunotherapy, and hopefully, as a result, identify new cancer immunotherapy targets,” she said. 

To that end, her team found that the interaction between the immune checkpoint protein PD-L2 and its binding partner RGMb impacts immunotherapy responses mediated by the microbiome. Blocking this pathway enhanced antitumor immune responses in mice, even in cancers that are typically resistant to PD-1 inhibitors, highlighting this strategy’s potential to improve outcomes in patients unresponsive to this class of drugs. 

Sharpe also employed the gene-editing technology CRISPR in her search for new immune checkpoints to screen for proteins of interest by systematically deleting genes in T cells and observing the effects. Through this approach, she identified STUB1 as a target that suppresses antitumor immunity via IL-27Rα signaling. Buoyed by her preclinical work, Sharpe continues to explore this promising avenue. 

Optimism and the Road Ahead 

In the early 1990s, the notion of using the immune system to fight cancer was considered by many to be a fool’s errand. Today, thanks to the pioneering work of Allison and Sharpe, among others, immune checkpoint inhibitors are improving outcomes for many cancer patients. Equally important, they helped build a foundation upon which future progress can be accelerated and new approaches can be developed for those that desperately need them. 

As Allison concluded, “We’re getting there, but we know we can do better.”