Enhanced detection of neoantigen-reactive T cells targeting unique and shared oncogenes for personalized cancer immunotherapy

Yossef, Rami; Tran, Eric; Deniger, Drew C.; Gros, Alena; Pasetto, Anna; Parkhurst, Maria R.; Gartner, Jared J.; Prickett, Todd D.; Cafri, Gal; Robbins, Paul F.; Rosenberg, Steven A.

doi:10.1172/jci.insight.122467

Cited by 187 publications

(154 citation statements)

References 43 publications

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“…205 Although previously thought to be rare, 19 the number of identified public neoantigens has rapidly increased in recent years. These include public neoantigens associated with common driver oncogenes, such as KRAS, 11,18,206,207 BRAF, 170 beta-catenin, 198 CDK4, 208,209 H3.3K27M, 210 and IDH1 211 as well as tumor suppressor genes, like TP53. 212,213 Whether immunogenic epitopes can be discovered for the 119 other known driver oncogenes 214 have provided in vivo evidence that infusion of public neoantigenspecific T cells can be associated with durable cancer regression in humans.…”

Section: Public and Private Cancer Neoantigensmentioning

confidence: 99%

“…Elucidating patient-specific private neoantigens in a manner that is at once rapid, scalable, and costeffective represents an unprecedented challenge. 215 Pre-clinical data suggests that preparative sorting of TIL or PBMC based on expression of co-inhibitory markers (PD1, TIM3, CD39) 159,207,216,217 or acute activation markers (CD134, CD137) 162,207,216 can enrich for neoantigen-specific T cells. ACT of TIL enriched for private neoantigen reactivity has resulted in durable CRs in a subset of patients with common solid cancers, including those arising from the bile duct, breast, and cervix.…”

Section: Public and Private Cancer Neoantigensmentioning

confidence: 99%

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T cell receptor‐based cancer immunotherapy: Emerging efficacy and pathways of resistance

Chandran

Klebanoff

2019

Immunological Reviews

237

185

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Adoptive cell transfer (ACT) using chimeric antigen receptor (CAR)‐modified T cells can induce durable remissions in patients with refractory B‐lymphoid cancers. By contrast, results applying CAR‐modified T cells to solid malignancies have been comparatively modest. Alternative strategies to redirect T cell specificity and cytolytic function are therefore necessary if ACT is to serve a greater role in human cancer treatments. T cell receptors (TCRs) are antigen recognition structures physiologically expressed by all T cells that have complementary, and in some cases superior, properties to CARs. Unlike CARs, TCRs confer recognition to epitopes derived from proteins residing within any subcellular compartment, including the membrane, cytoplasm and nucleus. This enables TCRs to detect a broad universe of targets, such as neoantigens, cancer germline antigens, and viral oncoproteins. Moreover, because TCRs have evolved to efficiently detect and amplify antigenic signals, these receptors respond to epitope densities many fold smaller than required for CAR‐signaling. Herein, we summarize recent clinical data demonstrating that TCR‐based immunotherapies can mediate regression of solid malignancies, including immune‐checkpoint inhibitor refractory cancers. These trials simultaneously highlight emerging mechanisms of TCR resistance. We conclude by discussing how TCR‐based immunotherapies can achieve broader dissemination through innovations in cell manufacturing and non‐viral genome integration techniques.

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Section: Public and Private Cancer Neoantigensmentioning

confidence: 99%

Section: Public and Private Cancer Neoantigensmentioning

confidence: 99%

T cell receptor‐based cancer immunotherapy: Emerging efficacy and pathways of resistance

Chandran

Klebanoff

2019

Immunological Reviews

237

185

View full text Add to dashboard Cite

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“…5), and economic ( Fig. 3B and C) [23][24][25][26][27][28][29][30][31][32] Kymriah (475,000 USD in US, 307,000 USD in Japan, 373,000 USD in UK), to establish a universal and viable therapeutic platform.…”

Section: Resultsmentioning

confidence: 99%

“…Because a significant fraction of antigenic mutations in human tumors are not shared between patients, most of the neoantigens are private antigens thus require personalized treatment. Combining whole-exome sequencing(WES) and bioinformatics analysis, personalized neoantigen-specific CAR-T cells were developed [25].…”

Section: The Tumor-antigen Specificity and Mutationmentioning

confidence: 99%

Adoptive CD8+ T cell therapy against cancer:Challenges and opportunities

et al. 2019

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“…Although tumor-reactive TIL candidates can be roughly enriched from tumor digests through the expression of cell-surface markers (e.g. PD-1) (Gros et al, 2016;2014a;Yossef et al, 2018) (Gros et al, 2016;2014b;Yossef et al, 2018), bystander T cells expressing such makers also exist in the tumor microenvironment (Duhen et al, 2018;Sade-Feldman et al, 2018;Scheper et al, 2019;Simoni et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Detecting Tumor Specific Antigen-Reactive T cells from Tumor Infiltrating Lymphocytes via Interaction Dependent Fucosyl-biotinylation

Liu

Chen

et al. 2020

Preprint

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HighlightsInteraction dependent fucosylation enables the detection and isolation of bona fide intratumoral tumor specific antigen-reactive T cells Tumor specific antigen-reactive CD8 + T cells possess capabilities to be expanded and adoptively transferred for tumor control Tumor specific antigen-reactive CD8 + T cells feature oligoclonal expansion and upregulate genes for the steroid biosynthesis and metabolic process Intratumoral bystander CD8 + T cells can be separated into two groups based on PD-1 expression that feature distinct gene modules SummaryRe-activation and clonal expansion of tumor specific antigen (TSA)-reactive T cells are critical to the success of checkpoint blockade and adoptive transfer of tumor-infiltrating lymphocyte (TIL) based therapies. There are no reliable markers to specifically identify the repertoire of TSA-reactive T cells due to their heterogeneous composition. Here we introduce FucoID as a general platform to detect endogenous antigen-specific T cells and study their biology. Through this interaction dependent labeling approach, TSA-reactive T cells can be detected and separated from bystander T cells in primary tumor digests based on their cell-surface enzymatic fucosylbiotinylation. Compared to bystander TILs, TSA-reactive TILs possess a distinct TCR repertoire and unique gene features. Though exhibiting a dysfunctional phenotype, this subset of TILs possesses substantial capabilities of proliferation and tumor specific killing. FucoID features genetic manipulation-free procedures and a quick turnover cycle, and therefore should have the potential of accelerating the pace of personalized cancer treatment.

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Enhanced detection of neoantigen-reactive T cells targeting unique and shared oncogenes for personalized cancer immunotherapy

Cited by 187 publications

References 43 publications

T cell receptor‐based cancer immunotherapy: Emerging efficacy and pathways of resistance

T cell receptor‐based cancer immunotherapy: Emerging efficacy and pathways of resistance

Adoptive CD8+ T cell therapy against cancer:Challenges and opportunities

Detecting Tumor Specific Antigen-Reactive T cells from Tumor Infiltrating Lymphocytes via Interaction Dependent Fucosyl-biotinylation

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