About

David Scheinberg, MD, PhD, is the Chair of the Center for Experimental Therapeutics at Memorial Sloan Kettering Cancer Center and the Deputy Director of the Sloan Kettering Institute for Therapeutic Discovery. His laboratory's overall goals are to develop novel targeted immunotherapies based on effectors of the immune system and to understand their mechanisms of action and resistance. His research includes the development of antibodies, targeted nano-devices, engineered cells, and active specific agents such as vaccines, with an emphasis on translating these therapies into human clinical trials. Notable contributions include the development of targeted alpha particle therapies, targeted beta emitters, oncogenic protein peptide vaccines, and humanized antibodies, all of which have reached human clinical trials. His team has also discovered TCR mimic antibodies to intracellular proteins, prototype targeted nano-machines, and cellular micropharmacies. Dr. Scheinberg specializes in caring for patients with leukemia and advancing new treatment strategies through innovative research.

Research topics

• Biology
• Computational biology
• Immunology
• Cancer research
• Biochemistry
• Genetics
• Cell biology
• Chemistry
• Medicine

Selected publications

• T-Cell Clonal Expansion in Peripheral Blood Following Interventional Radiology Procedures for Metastatic Liver Cancer

  Cancers · 2026-05-04

  articleOpen access

  BACKGROUND: Interventional radiology (IR) procedures may induce anti-tumor immune responses, with subsequent clonal expansion of specific T-cells recognizing tumor antigens. This exploratory study aims to investigate the clonal expansion of T-cells in the peripheral blood after interventional radiology procedures for metastatic liver cancer. METHODS: This prospective study included 16 patients with metastatic liver cancer undergoing IR procedures (13 embolizations and 3 ablations). Biopsy samples were collected prior to the procedure, and peripheral blood samples were obtained both pre- and post-procedure. Bulk T-cell receptor (TCR) sequencing was conducted to assess T-cell clonality dynamics and to evaluate the impact of procedures on the T-cell repertoire. RESULTS: = 0.27-0.77). A subset of patients exhibited limited T-cell clonal expansion in peripheral blood one month after IR procedures, with more than 10 T-cell clonotypes expanding in 43% of patients. Most clonal expansions decreased in frequency by three months; however, 3 patients displayed persistently expanding T-cell clonotypes in peripheral blood ≥ 3 months following IR procedures. CONCLUSIONS: IR procedures do not alter the overall clonality of the T-cell repertoire but may promote the expansion of a limited number of clonotypes. This study demonstrates that it is feasible to detect and longitudinally track expanding T-cell clonotypes following IR liver-directed therapy. Further studies are needed to determine whether these expanding clonotypes contribute to systemic anti-tumor immunity.

  PublisherOA PDFDOI

• Abstract 3714: Immunopeptidomic discovery of fetal WNT-associated antigen NKD1 enables HLA-A2+ restricted TCR-T therapy for MSS mCRC

  Cancer Research · 2026-04-03

  articleSenior author

  Abstract T cell-engaging therapies have achieved limited success in microsatellite stable (MSS) metastatic colorectal cancer (mCRC), in part because of a paucity of truly cancer-specific targets. Systematic interrogation of the immunopeptidome, the repertoire of peptides presented by human leukocyte antigen (HLA) class I molecules, can expand the pool of druggable antigens beyond conventional surface receptors. Nonetheless, both neoantigenic driver mutations and recently described oncofetal peptides are rare or absent in most CRCs. Our recent work shows that mCRC cells adopt a highly stereotyped fetal-like phenotype, characterized by activation of a developmental WNT signaling program that is further enriched in metastasis-initiating cells and conserved across diverse patients. We hypothesized that this transcriptional reprogramming generates a cancer-specific, developmentally fixed HLA-I ligandome that can be exploited for T cell therapy. Using an integrated platform for systematic collection and multimodal profiling of matched normal colon, primary tumor, and metastases from patients undergoing CRC surgery, we established ex vivo patient-derived organoids (PDOs) that faithfully capture patient-specific CRC cell states and provide an effectively inexhaustible source of tumor cells for immunopeptidomic discovery and functional validation. In HLA-A2+ PDOs, representing the most common HLA allele, immunopeptidomic analyses identified recurrent presentation of peptides derived from fetal WNT program genes, in particular NKD1, that are prevalent across mCRC PDOs from HLA-A2+ patients and undetectable in healthy tissues. These peptides were immunogenic in vitro, eliciting robust reactivity from healthy donor T cells and supporting their suitability as therapeutic targets. Moreover, naive CD8+ T cells engineered with NKD1-specific T cell receptors (TCRs) showed strong cytokine activation and potent, antigen-dependent cytotoxicity against mCRC PDOs without detectable off-target activity, consistent with a favorable therapeutic index. Together, these data nominate NKD1 as a conserved antigen in mCRC and support the clinical advancement of an NKD1-directed TCR-T cell product as a first-in-class precision therapy for patients with MSS mCRC. Citation Format: Jaeyop Lee, Swara Patel, Iñaki Etxeberria, Elizabeth Benitez, Jura Pintar, Andres Rettig, Christopher Cowley, Stefanie Gerstberger, Kathleen Luckett, Asha Saxena, Zita Aretz, Tatyana Korontsvit, Zhuoning Li, Kevin Soares, Emmanouil Pappou, T. Peter Kingham, William Jarnagin, Philip B. Paty, Martin R. Weiser, Michael D’Angelica, Julio Garcia-Aguilar, Jinru Shia, Mara Monetti, Christopher A. Klebanoff, Karuna Ganesh, David A. Scheinberg, . Immunopeptidomic discovery of fetal WNT-associated antigen NKD1 enables HLA-A2+ restricted TCR-T therapy for MSS mCRC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3714.

  PublisherDOI

• Abstract 6982: Patient-derived uveal melanoma organoids reveal HLA-I-restricted tumor antigens and tumor-reactive T cells

  Cancer Research · 2026-04-03

  article

  Abstract Background: Uveal melanoma (UM) is a rare but aggressive melanoma subtype with limited response to immune checkpoint inhibitors. Identifying tumor-specific or associated antigens and tumor-reactive T cells is critical to advancing precision immunotherapy. Patient-derived tumor organoids (PDOs) offer a physiologically relevant ex vivo model to study tumor-immune interactions and to uncover novel therapeutic targets. Methods: PDOs were established from fine-needle aspiration biopsies of five patients with metastatic UM. HLA-I-restricted immunopeptidomes were successfully characterized in three PDOs through immunoprecipitation of HLA-peptide complexes followed by mass spectrometry (MS). Identified peptides were matched against the UniProt human reviewed database. Dissociated tumor cells from one PDOs were treated with IFN-γ to enhance antigen presentation and then co-cultured with autologous peripheral blood mononuclear cells (PBMCs) for sequential stimulations over four weeks. After a third stimulation, CD8+ T cells were analyzed by flow cytometry and subjected to single-cell RNA and paired V(D)J sequencing using the 10x Genomics platform to define phenotypes and clonotypes of activated T cells. Tumor-reactive TCR clonotypes were identified, and their CDR3β sequences were analyzed using the TCRMatch tool in the IEDB database to assess sequence homology and potential antigen specificity. Results: Immunopeptidomic analysis identified 3,628, 6,735, and 10,407 unique 8-11mer peptides across three PDOs. Shared tumor-associated antigens (TAAs) included CSPG4, TYRP1, SLC45A2, OCA2, PMEL, TYR, MLANA, and SOX10. T-cell activation assays demonstrated that 12.3% of CD8+ T cells exhibited HLA-I-dependent activation upon restimulation with autologous PDOs, which was abrogated by HLA-I blockade. Single-cell RNA sequencing of CD8+ T cells in the co-culture revealed activated cytotoxic clusters unique in the restimulated cells, characterized by high expression of CD137, GZMH, MIR155HG, PKM, and LAG3. TCR clonotype analysis using TCRMatch identified candidate tumor-reactive TCRs possibly recognizing PMEL, MART-1, and MAGEA10. Conclusions: This study demonstrates the feasibility of using PDOs from metastatic UM to define the HLA-I-restricted immunopeptidome and to identify tumor-reactive T-cell clonotypes through autologous PDO-PBMC co-culture. The integration of immunopeptidomics with single-cell RNA/TCR sequencing provides a robust framework for mapping patient-specific tumor-immune interactions. Identified TAAs and tumor-reactive TCRs represent potential biomarkers and targets for next-generation precision immunotherapies, including personalized tumor vaccines and TCR-based adoptive cell therapies. Citation Format: Alexander Lim, Wei Tian, Zhuoning Li, Mara Monetti, Alexander Noor Shoushtari, James Smithy, Samuel Tischfield, Mark Donoghue, David A. Scheinberg, Chenyang Zhan. Patient-derived uveal melanoma organoids reveal HLA-I-restricted tumor antigens and tumor-reactive T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6982.

  PublisherDOI

• Trispecific targeting of T cells engineered with TCR mimic antibodies to limit antigen escape

  Journal for ImmunoTherapy of Cancer · 2026-01-01

  articleOpen accessSenior author

  BACKGROUND: Antigen loss and tumor heterogeneity present significant challenges for successful immunotherapies. T-cell receptor (TCR)-based therapies rely on the recognition of epitopes derived from intracellular tumor proteins presented by major histocompatibility complex class I molecules on cell surface. Solid tumor cells frequently lack immunoproteasomes, which are crucial for processing and presenting certain immunogenic epitopes. An effective strategy to mitigate the risk of antigen absence and tumor heterogeneity is to simultaneously target multiple tumor antigens, thereby providing critical rescue from disease relapse. Previously, we engineered a TCR mimic monoclonal antibody (TCRm) "ESK2", specific for Wilm's tumor 1 (WT1)-derived epitope RMFPNAPYL (RMF) in the context of HLA-A2, into a new chimeric antigen receptor T-cell format, antibody-TCR receptor (AbTCR)-chimeric signaling receptor (CSR). However, the RMF epitope is largely dependent on processing by the immunoproteasomes, which can be lost from leukemia cells and sometimes absent in solid tumor cells. METHODS: To mitigate antigen loss, tumor heterogeneity and broaden the reach of AbTCR T cells, we combined ESK2 with a new TCRm for an immunoproteosome-independent epitope derived from WT1, VLDFAPPGA (VLD), in the context of HLA-A2 molecules, named ESK3. ESK2 and ESK3 were tandemly engineered into one AbTCR-CSR construct, simultaneously recognizing both the WT1 RMF and VLD epitopes. To add additional specificity and potency, a CSR in these cells was engineered with a single chain variable fragment (scFv) for either CD33 to treat leukemia or mesothelin to treat solid tumors. The specificity and efficacy of the AbTCR-CSRs were evaluated in both in vitro and in vivo. RESULTS: In vitro studies demonstrated that the Tri-AbTCR-CSR (CD33 CSR) T cells showed the best killing activity against most acute myeloid leukemia cells. Similar levels of cytotoxicity were exhibited by ESK3 AbTCR-CSR (mesothelin CSR) against most solid tumor cell lines when compared with the Tri-AbTCR or a combination of ESK2 and ESK3 AbTCR-CSR. In animal therapy models, trispecific AbTCR-CSR T cells showed efficacy equivalent to single ESK2-AbTCR or ESK3-AbTCR-CSR T cells, against hematopoietic or solid tumor cells, further supporting the advantage of triple targeting strategy, overcoming epitope loss variants. CONCLUSIONS: Trispecific T cells targeting immunoproteasome-dependent and independent epitopes of WT1 peptide/HLA-A2 complexes, plus a CSR recognizing a third tumor-associated antigen, present an effective and cost-efficient approach for overcoming tumor immune evasion.

  PublisherDOI

• Abstract 585: Utilizing CAR T cell-derived exosomes for radiotheranostic applications

  Cancer Research · 2025-04-21 · 1 citations

  article

  Abstract Chimeric antigen receptor (CAR) T cell therapy is limited by antigen escape, poor solid tumor penetration, and an off-tumor toxicity profile. CAR T cell-derived exosomes have been shown to express the parental CAR construct, allowing tumor targeting but limited inherent anti-tumor effects alone. Further engineering CAR T cells to modify their exosome cargo, such as to bind anti-tumor drugs or radionuclides, may allow for the generation of novel targeted delivery vehicles for cancer therapy. We previously engineered humanized C825 (huC825), an anti-metal-DOTA-hapten single chain variable fragment (scfv), into multiple different constructs, one of which is the 4h11 CAR against MUC16/Cancer Antigen 125, developed by Brenjens lab at Memorial Sloan Kettering Cancer Center. We showed that huC825 allows for theranostic potential based on high-affinity binding to various chelated radionuclides, such as for alpha or beta particle-based radiotherapy or diagnostic imaging. We derived exosomes from 4h11 and huC825-4h11 CAR T cells, as well as untransduced T cells, and characterized them for CAR and huC825 expression using Western blot and radio thin layer chromatography (radio-TLC), respectively, as well as with direct stochastic optical reconstruction microscopy (dSTORM). We performed binding and cytotoxicity assays in vitro after radiolabeling and purifying the exosomes with size-exclusion chromatography (SEC), or using a pretargeted approach, with various chelated radiotracers. 4h11 and huC825-4h11 CAR T cell exosomes were reliably manufactured from parental CAR T cells with high transduction rates (80-95%). Western blot using CD81 and ALIX exosomal markers illustrates that 4h11 and huC825-4h11 CAR T cell exosomes and their parental CAR T cells are positive for the 4h11 CAR. dSTORM imaging shows huC825-4h11 exosomes are positive for both 4h11 and huC825. Radio-TLC illustrates that radionuclides chelated by Y-aminobenzyl-1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid, further referred to as aminobenzyl-DOTA (ABD), such as [161Tb]Tb-ABD (therapeutic metal) or [177Lu]Lu-ABD (diagnostic and therapeutic), exhibit significant binding to huC825-4h11 CAR T cell exosomes compared to controls. We optimized a method for radiolabeling huC825-4h11 exosomes and purifying the product with SEC using various DOTA-chelated radionuclides. In vitro radiotracer binding assays using SKOV3 human ovarian cancer cells overexpressing MUC16 illustrate that only huC825-4h11 CAR T cell-derived exosomes selectively bind both MUC16-expressing tumor cells and DOTA-chelated radionuclides. Our work illustrates the potential of huC825-4h11 CAR T cell-derived exosomes as delivery vehicles for radionuclides for imaging or targeted therapy. Their 50-160 nm size may allow better solid tumor penetration in vivo than current cellular treatment modalities. Future directions include in vivo imaging and radiotherapy studies. Citation Format: Sarah Qureshy, Leah Gajecki, Darren Veach, Sang Gyu Lee, Irina Matei, Lukas Carter, David Lyden, David Scheinberg, Simone Krebs. Utilizing CAR T cell-derived exosomes for radiotheranostic applications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 585.

  PublisherDOI

• Immunotheranostics in Solid Tumors: Longitudinal Tracking of Human IL13Rα2 CAR-T Cells In Vivo

  Journal of Nuclear Medicine · 2025-12-30

  articleOpen access

  Chimeric antigen receptor (CAR)-T cell therapy has shown limited success in the treatment of solid tumors, reinforcing the need to elucidate the in&nbsp;vivo biodistribution of these engineered T cells. Here, we integrate the anti-DOTA huC825 reporter (“Thor”) platform into newly developed human anti–interleukin-13 receptor α-2 (IL13Rα2)–single-cell fragment variable (scFv)–derived CAR-T cells and investigate its utility for mapping CAR-T cell distribution in a xenograft mouse model of melanoma. <b>Methods:</b> We engineered anti–IL13Rα2-scFv–derived CAR-T cells expressing huC825 (KLG3BBz-huC825), evaluated detection sensitivity, and monitored CAR-T cell biodistribution via weekly [⁸⁶Y]Y-aminobenzyl-DOTA PET/CT and therapeutic efficacy. <b>Results:</b> KLG3BBz-huC825 T cells demonstrated potent antigen-specific cytotoxicity and cytokine release in&nbsp;vitro. The Thor radiohapten capture platform offered exquisite detection sensitivity of only 3,000 engineered T cells and enabled prolonged spatiotemporal assessment of CAR-T cell kinetics up to 7 wk after infusion, corroborated by histopathology. Treatment with KLG3BBz-huC825 resulted in an overall survival benefit. <b>Conclusion:</b> The Thor platform offers a versatile and highly sensitive approach to study the real-time kinetics of CAR-T cells in&nbsp;vivo.

  PublisherOA PDFDOI

• 255 Noninvasive tracking of IL13Rα2 CAR-T cells with immunoPET reveals spatiotemporal dynamics and persistence in a melanoma model

  Regular and Young Investigator Award Abstracts · 2025-11-01

  articleOpen access
  PublisherOA PDFDOI

• Microenvironment actuated CAR T cells improve solid tumor efficacy without toxicity

  Science Advances · 2025-01-22 · 19 citations

  articleOpen accessSenior authorCorresponding

  A major limiting factor in the success of chimeric antigen receptor (CAR) T cell therapy for the treatment of solid tumors is targeting tumor antigens also found on normal tissues. CAR T cells against GD2 induced rapid, fatal neurotoxicity because of CAR recognition of GD2 + normal mouse brain tissue. To improve the selectivity of the CAR T cell, we engineered a synthetic Notch receptor that selectively expresses the CAR upon binding to P-selectin, a cell adhesion protein overexpressed in tumor neovasculature. These tumor microenvironment actuated T (MEAT) cells ameliorated T cell infiltration in the brain, preventing fatal neurotoxicity while maintaining antitumor efficacy. We found that conditional CAR expression improved the persistence of tumor-infiltrating lymphocytes because of enhanced metabolic fitness of MEAT cells and the infusion of a less differentiated product. This approach increases the repertoire of targetable solid tumor antigens by restricting CAR expression and subsequent killing to cancer cells only and provides a proof-of-concept model for other targets.

  PublisherDOI

• Abstract B007: Targeting the evolving immunopeptidome of metastatic colorectal cancer

  Cancer Immunology Research · 2025-02-23 · 1 citations

  article

  Abstract Chimeric antigen receptor (CAR) T cell therapies have achieved limited success in solid tumors, in part due to challenges in identifying cancer-specific targets. Investigating the immunopeptidome, peptides presented by human leukocyte antigen (HLA) class I molecules, offers an opportunity to expand the repertoire of targetable antigens. Recent findings reveal that metastatic colorectal cancer (mCRC) cells adopt a highly stereotyped fetal-like phenotype, characterized by the activation of a developmental WNT-signaling signature as a mechanism of cell-fate reprogramming. This transcriptional signature, accentuated in metastasis-initiating cells and conserved across diverse patients, is hypothesized to translate into a cancer-specific immunopeptidome. Utilizing an integrated platform, we collected and analyzed resected normal colon, primary tumor, and metastatic lesions from CRC patients, establishing patient-derived organoids (PDOs) that recapitulate CRC cell states ex vivo. Mass spectrometry profiling of PDOs from HLA-A*02:01+ patients identified peptide targets derived from fetal WNT-pathway gene states, referred to as oncofetal protein 1 (OFP1). These peptides were specific to CRC, absent in healthy tissues, and demonstrated immunogenicity through healthy donor T cell reactivity and expansion assays. To further harness these findings, we aim to systematically profile the immunopeptidome evolution from normal colon to metastatic CRC to identify conserved CRC-specific peptides for therapeutic targeting. Furthermore, we employed large-scale yeast display technology to isolate peptide-centric T cell receptor mimics (TCRms) that specifically recognize OFP1 peptides presented by HLA-A*02:01. Preliminary results demonstrate the successful isolation of OFP1-specific, HLA-A02:01-restricted TCRms, paving the way for the development of TCRm-based CAR T cells tailored for CRC therapy. This work provides the first comprehensive atlas of immunopeptidome evolution in CRC, elucidates CRC-specific intracellular molecular signatures as potential therapeutic targets, and advances the preclinical development of TCRm-engineered CAR T cells, paving the way for precision immunotherapies in metastatic CRC. Citation Format: Jaeyop Lee, David A Scheinberg, Karuna Ganesh. Targeting the evolving immunopeptidome of metastatic colorectal cancer [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B007.

  PublisherDOI

• Breaking barriers: ECM-degrading CAR T cells for enhanced efficacy in solid tumors 4516

  The Journal of Immunology · 2025-11-01

  articleOpen accessSenior author

  Abstract Description Chimeric antigen receptor (CAR) T cell therapy has transformed cancer treatment. Yet, its effectiveness against solid tumors is hindered by limited infiltration into the dense extracellular matrix (ECM) and the immunosuppressive tumor microenvironment (TME). To address these challenges, we developed Matrix-degrader Armored CAR T Cells Hacking Established Tumor microEnvironment (MACHETE), engineered to secrete ECM-degrading proteins. These proteins actively disrupt the ECM, enhance T cell infiltration, and mitigate fibrosis-associated immunosuppression. In vitro, MACHETE demonstrated superior cytotoxicity in both 2D and 3D tumor co-culture systems. In pancreatic cancer spheroid models, MACHETE exhibited significantly enhanced infiltration by effectively disrupting ECM architecture. Moreover, the secreted proteins exhibited intrinsic cytotoxic properties and antagonized TGF-β1, a key immunosuppressive cytokine in the TME, further boosting MACHETE’s efficacy. Importantly, we showed that this armoring strategy was broadly applicable across CAR/TCR platforms targeting diverse solid tumors, including breast, ovarian, and pancreatic cancers. In vivo study is ongoing to validate MACHETE’s ability to improve tumor infiltration, reprogram the TME, and enhance therapeutic efficacy. These findings underscore the potential of MACHETE as an innovative approach to overcoming the major barriers in CAR T cell therapy for solid tumors and support its translation into clinical applications. Funding Sources Supported by NIH R35241894. Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)

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Recent grants

• Project 4: Using Synthetic Immunology to Improve Activity and Specificity, and Overcome Resistance, in Cellular Therapy

  NIH · $138.0M · 1997–2025

• Understanding and Mimicking TCR Recognition with Therapeutic Monoclonal Antibodies.

  NIH · $6.1M · 2020–2027

• NIH Grant U01CA058260

  NIH · $937k · 1996

• Improving specificity of therapeutic antibodies for cancer.

  NIH · $8.5M · 1991–2020

• NIH Grant P01CA033049

  NIH · $39.8M · 2011

Frequent coauthors

• Tao Dao

  Memorial Sloan Kettering Cancer Center

  195 shared

• Michael R. McDevitt

  Memorial Sloan Kettering Cancer Center

  181 shared

• Ron S. Gejman

  139 shared

• Christopher M. Bourne

  University of Pennsylvania

  138 shared

• Joseph G. Jurcic

  130 shared

• Martin G. Klatt

  Charité - Universitätsmedizin Berlin

  118 shared

• Megan M. Dacek

  115 shared

• Stanley R. Frankel

  113 shared

Labs

• The David Scheinberg LabPI