Cancer immunotherapy — NIH Funding Overview

Why this matters now

Following the FDA approvals of pembrolizumab (2014), CAR-T therapies (2017–present), and TIL therapy (2024), NIH has reorganized significant fractions of its translational portfolio toward mechanism-of-resistance research, biomarker discovery, and rare-tumor application. The Cancer Moonshot reauthorization in 2023 reinforced this direction.

How NIH funds this area

NCI mechanisms commonly seen in this space include R01, R37 (MERIT), U01 (cooperative), P01 (program project), SPORE (P50), and U54 (specialized centers). The data below shows awards mentioning cancer immunotherapy across all NIH institutes.

Yearly NIH Awards for Cancer immunotherapy

Counts and total funding per fiscal year from NIH RePORTER. Recent fiscal years may understate final totals because of reporting lag.

Open the full interactive trends view for Cancer immunotherapy →

Top NIH Institutes (last 90 days)

Which NIH institutes funded the most Immunotherapy projects in the most recent 90-day window.

Common Activity Codes (last 90 days)

Which grant mechanisms (R01, R21, U01, P30, etc.) appeared most often for Immunotherapy in the recent period.

Most Active Institutions (last 90 days)

Universities and research organizations with the most Immunotherapy awards in the most recent 90-day window.

1. DANA-FARBER CANCER INST — 4 awards
2. UNIVERSITY OF TX MD ANDERSON CAN CTR — 3 awards
3. UNIVERSITY OF COLORADO DENVER — 3 awards
4. UNIVERSITY OF CALIFORNIA, SAN FRANCISCO — 3 awards
5. COLUMBIA UNIVERSITY HEALTH SCIENCES — 3 awards
6. WASHINGTON UNIVERSITY — 3 awards
7. UNIVERSITY OF PENNSYLVANIA — 3 awards
8. UNIVERSITY OF FLORIDA — 2 awards

Recently Awarded Cancer immunotherapy Grants

Twelve most recent awards mentioning Immunotherapy, drawn from NIH RePORTER. Click through to Find PIs for the full investigator search.

• Reversing cancer immunosuppression using attenuated Listeria monocytogenes

  5R01CA283604-03
  DANIEL PORTNOY · UNIVERSITY OF CALIFORNIA BERKELEY, CA · $473,641 · awarded Apr 21, 2026 · R01

  PROJECT SUMMARY The past decade has witnessed a breakthrough in cancer immunotherapy, from checkpoint inhibitors to adoptive T cell therapies, a new pillar in our armament of anti-cancer drugs now exists. However, our current therapies are based on the premise that adaptive immunity alone, mediated by activated T cells, can eliminate tumors. While the generation of anti-tumor T cells is paramount, many additional factors must be considered in an immune response, including access of therapies to solid tumors, the role of innate immunity, and the suppressive tumor microenvironment (TME). Microbial-based cancer therapies have the potential of addressing all of these challenges that can impede the success of immunotherapy. This proposal is based on extensive preclinical and clinical experience using an attenuated (DactA) strain of Listeria monocytogenes as a therapeutic cancer vaccine. In this proposal, we focus on the direct impact of L. monocytogenes (Lm) on shaping the immune phenotype of the TME. We find that injection of Lm intratumorally (IT) results in profound changes in the TME, including the reduction of Tregs which we trace to activation of TLR2. Surprisingly, bacteria injected IV also localize to tumors, but while bacteria in the liver and spleen are eliminated, bacteria injected both IT and IV, persist indefinitely in the tumors, although neither treatment results in reduction of tumor volume. However, mice previously immunized with Lm followed by IT injection, dramatically reduce the tumor burden, which we show requires CD8+ T cells. Based on our preliminary data, we hypothesize that Lm injected either IT or IV localizes and persists in tumor and increases the inflammatory milieu. Upon prior immunization, influx of Lm-specific CD8+ T cells mediate clearance of both the remaining bacteria and substantial shrinkage of the tumor, although the mechanism remains to be determined. Collectively these data reveal the importance of both innate and adaptive immunity in mediating a productive response to the tumors.

• CD4 helper programs that regulate intratumoral immunity

  5R01CA300217-02
  Alice Kamphorst · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI, NY · $532,970 · awarded Apr 17, 2026 · R01

  SUMMARY Immunotherapies have changed the landscape of cancer treatment, but remain mostly focused on CD8 T cells. In liver cancer patients, we found that in addition to expansion of PD-1+ effector- like CD8 T cells, expansion of CD4 T cells with similarities to follicular helper cells (Tfh) was associated with response to PD-1 targeted therapy. Tfh-like were found in close association to progenitor exhausted CD8 T cells and activated dendritic cells. Overall, our data in patients suggest that CD4-helpers may promote intratumoral differentiation of progenitor exhausted CD8 T cells into effector-like CD8 T cells that control tumor growth. The role of CD4-help in priming is well established, but the role of conventional CD4 T cells in sustaining effective anti-tumor responses and contributing to PD-1 targeted therapy needs to be better understood. In this study, using an autochthonous immunogenic mouse model of liver cancer, we propose to define the key cell-intrinsic features and cell interactions of anti-tumor CD4 T cells that promote anti-tumor immunity and enhance responses to PD-1 targeted therapy. In Aim 1, we will study transcriptional programs and secreted factors in CD4-helper T cells that aid anti-tumor immune responses. In Aim2, we will address how PD-1 signaling modulates tumor-specific CD4 T cells. In Aim3, we will identify CD4-helper interacting partners, and how CD4-help affects cell interactions of tumor-specific CD8 T cells. Given that the frequency Tfh-like in patients' tumors was corelated with plasma cells, we will specifically address the contribution of B cells (and the role of antibodies) in modulating anti-tumor responses, including phenotype of tumor-specific CD4 T cells. Finally, we will address the role of dendritic cells interactions with CD4 T cells, beyond T cell priming, to assess whether CD4-licensing is required for effective response to PD-1 targeted immunotherapy. Understanding what are the key interactions and signals that promote persistent T cell responses in tissues is critical to improve therapies for conditions mediated by chronic T cell stimulation. .

• Adipocyte PD-L1 in the Breast Tumor Microenvironment

  5R01CA279566-03
  Rong Li · GEORGE WASHINGTON UNIVERSITY, DC · $660,030 · awarded Apr 17, 2026 · R01

  ABSTRACT Programmed death-ligand 1 (PD-L1) and its receptor, programmed cell death protein 1 (PD-1), modulate anti-tumor immunity and are major targets of current checkpoint blockade immunotherapies. However, clinical trials of αPD-L1/αPD-1 antibodies in breast cancer to date have demonstrated only limited efficacy. The importance of a breast-specific tumor microenvironment (TME) in regulating anti-tumor immunity is vastly under- explored. Given the abundance of adipocytes in breast tissue, the well-documented association between adiposity and breast cancer-related mortality, and the emerging obesity paradox in anticancer immunotherapy, it is imperative to investigate the molecular underpinnings of the complex adipose-immune-tumor network within the adipocyte-rich breast TME. We recently identified a previously unappreciated, functionally significant source of PD-L1 in white adipocytes. Adipocyte PD-L1 is markedly induced during adipogenesis and obesity-related chronic inflammation. Using an adipocyte-specific knockout mouse model, we demonstrate an important role of adipocyte PD-L1 in promotion of tumor growth and attenuation of anti-tumor immunity. Furthermore, our preliminary data indicate physical and functional interactions between PD-L1 and lipid metabolism-related proteins and pathways in adipocytes, which suggests an adipocyte-intrinsic function of PD-L1. Based on our preliminary data, we hypothesize that adipocyte PD-L1 impedes anti-tumor lymphocytes and/or abets tumor cells through a lipid metabolism-related mechanism. We further propose that this action of adipocyte PD-L1 is particularly important at the tumor margin of immune-excluded tumors, where adipocytes are in proximity with both tumor and immune cells. We will combine our established tools and expertise in cancer biology, tumor immunology, and transcriptional regulation to validate this novel hypothesis through the following Aims: (1) Delineate how adipocyte PD-L1 mediates adipose-immune-tumor crosstalk, (2) Determine how adipocyte PD-L1 expression is regulated, and (3) Determine how adipocyte PD-L1 impacts immunotherapy in obese vs non-obese hosts. Our studies on adipocyte PD-L1 signaling in lipid metabolism will provide new molecular explanations for PD-L1 action in tumor immunology, a clear departure from the prevailing paradigm regarding tumor/immune PD-L1 actions. This proposed work represents a conceptual advance toward understanding the spatial landscape of the breast TME in immune regulation and tumorigenesis – a clinically relevant yet mechanistically under-explored problem. Our results could lay a solid foundation for developing new tools that predict and enhance therapeutic response to aPD-1/aPD-L1 immunotherapy for breast cancer patients, especially those with obesity.

• Adverse gut microbiome promotes resistance immune checkpoint inhibitors via chronic inflammation

  4R00CA296940-02
  Erez Baruch · UNIVERSITY OF TX MD ANDERSON CAN CTR, TX · $248,658 · awarded Apr 17, 2026 · R00

  Project summary/abstract Immune checkpoint inhibitors (ICI) transformed oncological care for multiple cancers. Yet, 80% of ICI patients will eventually fail therapy. Colossal efforts are invested in overcoming ICI resistance. A promising candidate is the gut microbiome which was associated with ICI clinical outcomes. I led a seminal clinical trial in which the gut microbiome of patients with ICI refractory metastatic melanoma was modulated via fecal microbiota transplantation (FMT). FMT and ICI re-induction resulted in increased intra-tumoral infiltration of CD8+ T-cells and objective clinical response rates of 30%. However, microbiome modulation remains far from wide clinical use. While FMT showed consistent clinical efficacy, it is not feasible outside of major academic centers; and some probiotics have been associated with a deleterious effect on ICI efficacy. Therapies that mimic the microbiome effect on the immune system can enhance ICI efficacy while omitting FMT obstacles. However, the development of such therapies is hindered since the mechanisms driving the gut microbiome's effect on anti-tumoral immunity remain unknown. In this proposal, I will test the hypothesis that an adverse microbiome induces a state of chronic inflammation that impedes ICI efficacy. FMT from donors with favorable microbiomes promotes anti-tumoral immunity by disrupting the net inflammatory signaling; hence, attenuating inflammation by direct immune re-programming can mimic the FMT effect. To test this, I propose the following research plan. In Aim 1, I will determine the effect of microbial-induced inflammation on anti-tumoral immunity by analyzing longitudinal stool, serum, gut, and tumor samples from a unique cohort of 33 patients with ICI- refractory melanoma (n=20) and microsatellite-instability high cancers (MSI-H, n=13) who participated in clinical trials of FMT and ICI re-induction (NCT03353402 and NCT04729322, respectively). Spatial transcriptomics of gut and tumor samples will be used to demonstrate FMT-induced immune dynamics and to test my sub-hypothesis that microbial inflammatory signals are mediated via myeloid antigen-presenting cells (APC). In Aim 2, I will determine the immune system's ability to override microbial signals. I will conduct FMT from cancer patients who responded and did not respond to ICI into CD11c-Cre+ Stat3f/f (Stat3Δ/Δ) mice that have dendritic cells with hyper-activated toll-like receptors (TLR) signaling. This experiment will test the ability of an immune system with a chronic inflamed state to overcome the beneficial effect of FMT from a donor with a favorable microbiome. To re-program the immune system to override the effect of adverse microbiome- mediated inflammation and hence overcome ICI resistance, I will compare the immune activity and tumor growth of mice undergoing FMT versus mice treated with a combination of ICI and interleukin (IL)-1b blockade; since IL-1b secretion can be a product of TLR activation and our previous work showed that an adverse microbiome induces IL-1-mediates gut inflammation. Overcoming ICI resistance by microbial-derived inflammatory signal blockade can enhance the clinical efficacy of ICI in patients with various cancer types.

• Targeting S1P-ACC Axis to Overcome MDSC Suppression

  5R01CA300284-02
  Shikhar Mehrotra · MEDICAL UNIVERSITY OF SOUTH CAROLINA, SC · $563,233 · awarded Apr 13, 2026 · R01

  ABSTRACT One of the key-confounding factors that hampers the adoptive T cell therapy is the presence of immunosuppressive cells like myeloid-derived suppressor cells (MDSCs), Tumor associated macrophages (TAMs) in the tumor microenvironment (TME). Thus, strategies to boost the anti-tumor T cell function in vivo by overcoming immunosuppression holds merit. In addressing the role of sphingolipids in TME we noted that MDSCs obtained from Sphingosine-kinase-2 knock-out (SphK2 KO) mice, and not SphK1 KO mice, had reduced immunosuppressive phenotype as evident from the increased proliferation and IFN-γ secretion by T cells co- cultured with SphK2 KO MDSCs. The reduced suppressive capacity of SphK2 KO MDSCs correlated to reduced expression of signature immunosuppressive molecules like Arginase, IDO, IL10, TGFβ whereas high levels of immunogenic cytokine IL12 compared to wild-type (WT) MDSCs. SphK2 KO MDSCs also exhibited upregulated expression of co-stimulatory molecules CD80, CD86, and MHC Class-I expression that correlated to the accumulation of fatty acids (FA) and enhanced activity of Acetyl CoA carboxylase (ACC), an enzyme that catalyzes conversion of acetyl CoA to malonyl CoA, a carbon donor for long chain FA synthesis. Since Acc1 is inactive when phosphorylated, we hypothesize that SphK2 mediated S1P regulates ACC activity, and its inhibition leads to increased fatty acid synthesis and immunogenic phenotype of the myeloid cells in the tumor microenvironment. Furthermore, inhibiting the MDSC suppressive function by pharmacological inhibition of SphK2 (using ABC294640) along with adoptive transfer of T cells and a checkpoint inhibitor (anti-PD1 antibody) improved the control of subcutaneously established B16-F10 melanoma. These observations have led us to propose the following specific aims for this project: 1) Determine how SphK2-mediated S1P induces MDSC suppressive phenotype, 2) Determine the mechanism of how SphK2-mediated S1P alters MDSC metabolism, and 3) Determine if SphK2 inhibition improves tumor control and enhances immunotherapy outcomes in vivo. These studies hold immense translational significance for patients with cancer where SphK2/S1P axis can be targeted to overcome immunosuppression and improve immunotherapeutic control of the tumors.

• Autumn Immunology Conference

  5R13AI129382-08
  SARAH D'ORAZIO · UNIVERSITY OF KENTUCKY, KY · $9,000 · awarded Apr 10, 2026 · R13

  This proposal requests 2 years of support for the Autumn Immunology Conference (AIC), an annual gathering of immunologists at the Marriott Downtown Magnificent Mile hotel in Chicago, IL. Year 1 will support the 52nd annual AIC on November 22-25, 2024 and Year 2 will support the 53rd annual meeting to be held November 21-24, 2025. The purpose of AIC is to foster communication and collaboration among immunologists, particularly those located in the middle of the US. Chicago is an exciting destination, and within driving distance for many midwestern academic institutions that are home to numerous NIAID-funded investigators. Since its inception in 1972, AIC continues to be very highly regarded and has a fiercely loyal group of regular attendees from across the US. The Specific Aims of AIC are to: 1) disseminate new immunological research findings from leading scientists in the field, 2) provide a forum for trainees to improve their presentation skills, and 3) increase interactions between scientists interested in immunology research. The meeting starts with a “Meet the Speakers” event for trainees, a Keynote speaker, and a welcome reception on Friday. Saturday & Sunday have similar schedules: morning symposia, then smaller themed breakout sessions, followed by posters. The meeting ends on Monday with just a morning plenary session. Each year, three different topic areas are chosen for the morning symposia. For 2024, twelve invited speakers will present talks on Innate Immunity, Immune Regulation at Barriers, & Mucosal Vaccines; the 2025 topics will be chosen by the AIC Chair in consultation with the Executive Council (EC) at the spring planning meeting. All accepted abstracts (typically ~270) are invited to give a 10 min. talk during the afternoon workshops, followed by a 1 h poster presentation. AIC is run by a dedicated all-volunteer group of faculty that serve multi-year terms including the “Leadership track” that consists of a 4 year commitment to serve as the Workshop Coordinator, the Secretary, the Chair, and then the Past Chair/Councilor. Another unique feature of AIC is the Undergraduate Workshop with a Careers in Immunology panel discussion and a table fair of PhD programs in Immunology. AIC is truly a formative experience for trainees and this remains one of the most positively evaluated aspects of the meeting. This year we will also expand our Wallace Fellows program, which has been providing travel awards and networking opportunities for trainees since 1972. The volunteer EC works hard to solicit external funding to support this meeting so we can keep the registration fee low, allowing as many trainees as possible to attend. In fact, the registration fee is waived for any undergrad who submits an abstract.

• Dietary regulation of anti-tumor immunity through caloric restriction

  5U01CA297713-02
  Russell Jones · VAN ANDEL RESEARCH INSTITUTE, MI · $767,324 · awarded Apr 9, 2026 · U01

  ABSTRACT OVERALL OBJECTIVE: The food we eat can affect tumor growth. Yet, it is unclear whether diets that alter nutrient levels in the tumor microenvironment (TME) primarily impact cancer cells or instead impact immune cells that provide critical defense against tumor progression. We have found that reducing overall calorie intake by 30–50%, a dietary regimen known as caloric restriction, antagonizes tumor growth by boosting anti-tumor immunity. Caloric restriction profoundly impacts the fate and function of CD8 T cells in the TME, favoring the activity of tumor-controlling T effector (Teff) cells while minimizing the accumulation of dysfunctional or “exhausted” T (Tex) cells. By studying how caloric restriction steers CD8 T cells between effector and exhausted fates, we will identify novel diet-regulated mechanisms that underpin CD8 T cell- mediated anti-tumor immunity and thus gain mechanistic insight into the epigenetic, transcriptional, and metabolic networks that link diet, lipid metabolism, and cancer progression. HYPOTHESIS: That the availability of ketone bodies versus fatty acids in the TME is a critical determinant of anti-tumor immunity. Our preliminary data indicate that caloric restriction antagonizes tumor growth by boosting anti-tumor CD8 T cell responses. These effects are lost when CD8 T cells cannot process ketone bodies, providing a mechanistic link between diet-regulated nutrients (ketone bodies) and anti-tumor T cell function. While caloric restriction and other diets can increase circulating levels of ketone bodies, some of these diets also increase circulating levels of fatty acids, which we hypothesize can negate or diminish the positive impact of ketone bodies on anti-tumor immunity. Our working model is that the balance between circulating levels of ketone bodies and fatty acids impacts ketone body-dependent metabolism and epigenetic programming in CD8 T cells and, by proxy, the balance between functional Teff cells (providing anti-tumor immunity) and dysfunctional Tex cells (dampening anti-tumor immunity) in the TME. SPECIFIC AIMS: (1) Determine how dietary fats influence anti-tumor T cell responses in the context of caloric restriction; (2) Determine how caloric restriction differentially controls T cell metabolism in the TME; and (3) Define how caloric restriction influences CD8 T cell fate decisions in the TME. IMPACT: Upon completion, this proposed research will have determined the mechanisms by which caloric restriction boosts CD8 T cell-mediated anti-tumor immunity, not only increasing the function of Teff cells but also decreasing the accumulation of dysfunctional (or “exhausted”) Tex cells in the TME. Our work will have laid the groundwork for defining dietary interventions with the power to boost the efficacy of immune checkpoint inhibitors (ICI) and diminish and/or reverse cancer progression.

• Defining the determinants of long term CAR-T persistence

  1R01CA300058-01A1
  Saar Gill · UNIVERSITY OF PENNSYLVANIA, PA · $703,071 · awarded Apr 9, 2026 · R01

  While some patients with previously untreatable blood cancers have achieved long-term remissions following CAR T cell therapy, others relapse after months to years. While engraftment and expansion are well characterized clinical surrogates of a durable anti-tumor effect, the attributes and origin of CAR T cells with prolonged function remain unknown. Prior research on CAR T cell-intrinsic properties in the treatment of hematologic malignancies has primarily focused on the manufactured product, but did not capture or define the T cell clones that are directly responsible for functional persistence and durable remissions. We have now found that long-lived CAR T cells up to 5 years post-infusion have a distinct CD4- CD8a- “double-negative” (DN) TCRαβ+ effector memory T cell phenotype. Our multimodal single-cell analyses have revealed that (i) the clones that eradicate leukemia in the initial phase differ from those that perform long term immunosurveillance, and that (ii) long lived DN CAR T cells show specific transcriptional signatures, with remarkable similarity to persistent CAR T cells in small cohort of children with B-ALL, to rare TCRαβ+ DN T cells from healthy donors, and to melanoma patients responding to dual checkpoint blockade. The CD4 and CD8 glycoproteins are co- receptors in TCR recognition of class II or class I major histocompatibility (MHC) – peptide complexes, respectively, serving to stabilize the TCR:peptide/MHC. Since DN T cells accumulate in chronic inflammatory diseases, these observations raise the intriguing possibility that in some settings, chronic antigen exposure can lead to a unique and previously under-appreciated T cell differentiation trajectory that is distinct from that found in “classic” CD8 T cell exhaustion. This dual PI proposal unites experts in immune cell therapies and evolutionary biology to test the overarching hypothesis that the fittest CAR T cells adopt a DN phenotype to withstand the demands of long-term immunosurveillance. In Aim 1 we will define the contribution of DN T cells to the long-lived CAR T cell population in patients with hematologic malignancies using flow cytometry and single cell multiomic analyses of CAR T cells persisting >12 months after infusion in patients with CLL, NHL, and MM. By leveraging our extensive cryorepository and well-annotated clinical trial outcome data we will be able to correlate CAR T cell phenotype to their functional persistence. In Aim 2 we will identify the cellular origin and evolutionary paths of long-lived CAR T cells. To distinguish the possibilities that persistent CAR T cells originated as true DN T cells vs. conventional T cells that downregulate the CD4 or CD8 co-receptors, we will use complementary approaches to trace DN persistent clonotypes back to their infusion origin. In Aim 3 we will determine whether and how DN T cells resist exhaustion during chronic stimulation, using a novel high-fidelity T cell exhaustion model along with gain- and loss-of function interventions to illuminate this biology. Together, these studies will illuminate the lineage relationships of various endogenous and engineered T cells and guide the development of more effective CAR T cell therapies.

• Physical Resistance to Immune Cell Attack by the Cellular Glycocalyx

  5R01CA276398-04
  Matthew Paszek · CORNELL UNIVERSITY, NY · $441,603 · awarded Apr 7, 2026 · R01

  Project Summary/Abstract Cancer cells construct a cellular glycocalyx with biochemical and biophysical attributes that protect against attack by effector immune cells. Currently, our mechanistic understanding of how the cancer-cell glycocalyx may physically interfere with any of the multiple pathways and individual steps of effector-cell mediated killing is highly limited. Our overarching hypothesis is that by developing a better physical understanding of the glycocalyx in resistance to immune cell attack, we can better devise new cellular engineering strategies to overcome the glycocalyx barrier. Our project will specifically focus on glycocalyx-mediated protection against attack by Natural Killer (NK) cells, which are attracting significant attention in the field of cancer immunotherapy. NK cells possess natural cytotoxic activity against tumor cells and can be further engineered with a chimeric antigen receptor (CAR) to target a specific tumor antigen. As such, NK cells are exciting candidates for adoptive cell therapy. Cell surface mucins are highly overexpressed in cancer and serve as primary structural elements of the glycocalyx. In this proposal, our aims are to (1) determine how specific molecular properties of mucins govern the glycocalyx structure and thereby mediate cellular resistance to NK-cell attack; (2) identify the specific mechanisms through which mucins physically disrupt NK and CAR-NK attack; and (3) develop NK cellular engineering strategies to overcome the mucin barrier. To complete our aims, we will employ state-of-the-art imaging approaches that our lab has developed for characterizing the nanoscale material structure of the glycocalyx. We also will take advantage of our lab’s expertise and validated tools for engineering the physical structure of the glycocalyx. Combining these imaging and cellular engineering strategies with established techniques in immune cell biology will enable new specific hypotheses regarding the physical functioning of the glycocalyx in protection against immune cell attack to be tested. They will also support the design and testing of engineered NK cells with structure-optimized CARs and glycocalyx-editing enzymes for improved elimination of mucin-bearing cancer cells. Adoptive cell therapy has tremendous promise for treating otherwise recalcitrant cancers. In part due to the technical challenges of manipulating and characterizing the physical structure of the glycocalyx, our physical understanding of the cancer-cell glycocalyx in resistance to adoptive cell therapy is poor. Our project will address this knowledge gap and test new strategies for NK engineering that, if successful, can be further developed for clinical applications.

• Proteolysis targeting chimera against nuclear receptor NR4A1 for melanoma therapy

  5R01CA290792-03
  Weizhou Zhang · UNIVERSITY OF FLORIDA, FL · $645,631 · awarded Apr 7, 2026 · R01

  Project Summary-Abstract Tumor microenvironment (TME) consists of many cell types that co-exist to promote tumor progression. Most cancer therapeutics are designed to target one molecule in one defined cell type. For example, vemurafenib (BRAF inhibitor) kills melanoma cells through targeting mutated BRAF; whereas pembrolizumab (anti-PD-1 antibody) blocks PD-1 on T cells, re-activating anti-tumor immunity. Our overarching goal is to identify targetable molecules/pathways that are critical for multiple cell types within the TME. Using the published single cell RNAseq (scRNAseq) datasets, we searched for these molecules/pathways meeting the following criteria: 1) they should have important functions in cancer cells and immune suppressive cell types such as regulatory T cells (Tregs), exhausted T cells (Texh), and myeloid-derived suppressor cells (MDSCs) etc.; 2) they are not important for effector function of major immune cells such as effect T cells (CD4+ or CD8+ Teff) or nature killer cells (NK); 3) they should be targetable with known inhibitors. NR4A1 fits all 3 criteria and represents a valid target for cancer immunotherapy. In the current proposal, we intend to use proteolysis-targeting chimera (PROTAC) technology to develop a first-of-its-kind NR4A1 degrader for melanoma therapy. Aim 1. Rational design of novel celastrol-based NR4A1-Ps by modifying celastrol and linkers. Aim 2. Determine cellular and molecular mechanisms by which NR4A1-Ps work to inhibit melanoma. Aim 3. Explore the therapeutic potential of NR4A1- Ps as a single agent or in combination. The outcome is to define the rationale for the future clinical translation of NR4A1-Ps to enhance ICI therapy responses in melanoma.

• Tumor-barcoding coupled with high-throughput sequencing for quantitative radiogenomics of the abscopal response in NSCLC

  7R01CA271540-04
  Phuoc Tran · UNIVERSITY OF TX MD ANDERSON CAN CTR, TX · $658,606 · awarded Apr 7, 2026 · R01

  Cancer immunotherapy (IMT) can produce robust and durable anti-tumor immune responses in some cases. However, many cancers are non-responsive to IMT and combination approaches need to be actively investigated, particularly in lethal tumors such as IMT-insensitive non-small cell lung cancer (NSCLC). Preclinical studies in general have been found to be poor predictors of success for IMT agents and chemoradiotherapy combinations in the clinic, likely due to poorly conceived and executed treatment protocols, dated disease model systems and lack of an existing framework for cross-validation of preclinical results. There is a need to develop a rigorous preclinical testing program for existing IMT agents combined with chemoradiation. NSCLC genetically engineered mouse models (GEMMs) of the major molecular NSCLC subtypes have been created. However, there are no NSCLC GEMMs that to our knowledge has demonstrated “abscopal” responses reliably to IMT, which is one unique strength of this current proposal. Also, a major limitation of existing GEMMs is the relatively small number of different genotypes that can be generated and their lack of quantitative precision. This proposal leverages a new technique, tumor barcoding with barcode deep-sequencing (Tuba-seq) and in vivo Cre-lox and CRISPR/Cre-mediated GEMMs to model oncogenesis and radiation-drug response with unprecedented precision and genomic-comprehensiveness. We are using this R01 mechanism in the present proposal via two Specific Aims stated below to test the following central hypotheses: (i) we hypothesize that treating with both anti-PD-L1 and a novel orally bioavailable ATR inhibitor (ATRi), AZD6738, in combination with chemoradiation will result in an improved and durable anti-tumor immune response in poorly immunogenic NSCLC GEMMs; and, (ii) Tuba-seq we will allow an unprecedented view of the radio-pharmacogenetic landscape of NSCLC responses in vivo. SPECIFIC AIM #1 – Establish a radio-pharmacogenetic map of oncogene-driven non-small cell lung cancer to both chemoradiation and combined chemoradiation/anti-PD-L1 therapy We propose to use novel CRISPR/Cre-mediated GEMMs of NSCLC to test the optimal combinations of chemoradiation with anti-PD-L1 IMT. We will then examine the mechanism of action of chemoradiation with IMT using multiparametric immunologic approaches and an innovative technique enabling lineage tracing and direct quantification of treatment effects on these different genetic backgrounds in vivo. SPECIFIC AIM #2 – Determine tumor cell genotype effects on combination anti-PD-L1 immunotherapy and ATRi with chemoradiotherapy in oncogene- driven non-small cell lung cancer. This Aim leverages our novel CRISPR/Cre-mediated GEMMs of NSCLC to test genotype effects on the combination of anti-PD-L1 and ATRi with chemoradiation. By using all these tools, we will be able to decode the major aspects of the molecular underpinnings of chemoradiation and combination IMT resistance in NSCLC, contributing to improved therapies and positively impacting patient outcomes.

• Optimizing outcomes for children and young adults with relapse of B-cell acute lymphoblastic leukemia after CD19-targeted chimeric antigen receptor T-cell therapy

  5K08CA277013-04
  Regina Myers · CHILDREN'S HOSP OF PHILADELPHIA, PA · $181,074 · awarded Apr 7, 2026 · K08

  PROJECT SUMMARY/ABSTRACT This K08 Award encompasses a research and training plan to facilitate Dr. Regina Myers' transition to an independent clinical investigator. Dr. Myers is currently an Instructor of Pediatrics and a pediatric oncology and cell therapy physician at Children's Hospital of Philadelphia and the University of Pennsylvania. Her long-term goal is to develop an independent research program that will integrate early phase clinical trials with advanced epidemiology methodologies in order to improve outcomes for children and young adults with high-risk hematologic malignancies. The training objectives for this award will bridge her prior experience in immunotherapy and outcomes research to her long-term goals, and include: acquiring independence in the design and implementation of early phase immunotherapy clinical trials, expanding her expertise in clinical epidemiology to include advanced methods for causal inference, establishing proficiency in the assessment of clinical trial correlative endpoints, and gaining experience with the application of synthetic control arms in pediatric cancer clinical trials. The proposed activities will be conducted in the resource-rich environment at CHOP/Penn and under the mentorship of an expert, multidisciplinary team led by Dr. Stephan Grupp, an international leader in cancer immunotherapy. CD19-specific chimeric antigen receptor-modified T cells (CAR19) have demonstrated unprecedented responses in relapsed or refractory B-cell acute lymphoblastic leukemia. Unfortunately, however, 50% of children and young adults relapse suffer a subsequent relapse and their prognosis after post-CAR19 relapse is dismal. As the use of CAR19 broadens, there is a corresponding increase in the number of patients with post-CAR19 relapse, creating a critical need to identify optimal salvage treatment approaches. The proposed research aims to improve outcomes after post-CAR19 relapse using novel and complementary clinical research approaches. In Aim 1, Dr. Myers will perform a phase 1/2 clinical trial to test a dual-antigen targeted CAR designed to overcome the primary mechanisms of CAR failure in children with post-CAR19 relapse. Secondary analyses will evaluate the predictive value of specific biomarkers for CAR failure and will compare the dual-targeted CAR against synthetic external control data. In Aim 2, Dr. Myers will assess the comparative effectiveness of existing treatment approaches for post-CAR19 relapse using randomized clinical trial emulation methods, leveraging clinical trial and real-world data from the largest, single-center pediatric CAR cohort. Successful completion of this career development award will advance the field through the introduction of a novel, dual-antigen targeted CAR and the establishment of a robust clinical research infrastructure capable of integrating real-world data with clinical trial data to determine optimal existing treatment strategies and efficiently assess new therapies as they become available. The proposed studies and training plan will provide an outstanding foundation for Dr. Myers' career as a physician-scientist.

Related topics

• CRISPR and gene editing
• Gene therapy