Novel and shared neoantigen derived from histone 3 variant H3.3K27M mutation for glioma T cell therapy

Chheda, Zinal; Kohanbash, Gary; Okada, Kaori; Jahan, Naznin; Sidney, John; Pecoraro, Matteo; Yang, Xinbo; Carrera, Diego; Downey, Kira; Shrivastav, Shruti; Liu, Shuming; Lin, Yi Ting; Lagisetti, Chetana; Chuntova, Pavlina; Watchmaker, Payal; Mueller, Sabine; Pollack, Ian F.; Rajalingam, Raja; Carcaboso, Ángel M.; Mann, Matthias; Sette, Alessandro; García, K. Christopher; Hou, Yayi; Okada, Hideho

doi:10.1084/jem.20171046

Cited by 189 publications

(181 citation statements)

References 58 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%

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%

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

Chandran

Klebanoff

2019

Immunological Reviews

237

185

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“…Further, the pool of brain tumor antigens amenable to CAR T cell targeting is expected to expand beyond membrane‐associated proteins. Chheda and colleagues discovered a shared neoantigen across DIPG patients derived from a mutation in the H3.3K27 . Stimulating HLA‐A2+, CD8+ T cells with the mutated peptide generated a TCR clone which, when expressed on T cells, mediated cytoxicity against tumor cells harboring the same mutation .…”

Section: Overcoming Tumor Heterogeneitymentioning

confidence: 99%

“…Chheda and colleagues discovered a shared neoantigen across DIPG patients derived from a mutation in the H3.3K27 . Stimulating HLA‐A2+, CD8+ T cells with the mutated peptide generated a TCR clone which, when expressed on T cells, mediated cytoxicity against tumor cells harboring the same mutation . Moreover, some recent studies have developed CARs against soluble proteins, indicating the potential to target brain tumor‐specific secreted factors.…”

Section: Overcoming Tumor Heterogeneitymentioning

confidence: 99%

CAR T cells for brain tumors: Lessons learned and road ahead

Akhavan

Alizadeh

Wang

et al. 2019

Immunological Reviews

173

161

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Malignant brain tumors, including glioblastoma, represent some of the most difficult to treat of solid tumors. Nevertheless, recent progress in immunotherapy, across a broad range of tumor types, provides hope that immunological approaches will have the potential to improve outcomes for patients with brain tumors. Chimeric antigen receptors (CAR) T cells, a promising immunotherapeutic modality, utilizes the tumor targeting specificity of any antibody or receptor ligand to redirect the cytolytic potency of T cells. The remarkable clinical response rates of CD19‐targeted CAR T cells and early clinical experiences in glioblastoma demonstrating safety and evidence for disease modifying activity support the potential of further advancements ultimately providing clinical benefit for patients. The brain, however, is an immune specialized organ presenting unique and specific challenges to immune‐based therapies. Remaining barriers to be overcome for achieving effective CAR T cell therapy in the central nervous system (CNS) include tumor antigenic heterogeneity, an immune‐suppressive microenvironment, unique properties of the CNS that limit T cell entry, and risks of immune‐based toxicities in this highly sensitive organ. This review will summarize preclinical and clinical data for CAR T cell immunotherapy in glioblastoma and other malignant brain tumors, including present obstacles to advancement.

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“…Because oncogenesis is often attributed to a driver mutation that can be shared across patients, neoantigens derived from driver mutations could be ideal T‐cell targets. In fact, several driver‐mutation derived neoantigens have been reported . However, the majority of somatic mutations are passenger mutations, which are specific to each individual in most cases, therefore the establishment of a reliable method for neoantigen detection is essential for future clinical application.…”

Section: Neoantigensmentioning

confidence: 99%

“…In fact, several driver-mutation derived neoantigens have been reported. 16,17 However, the majority of somatic mutations are passenger mutations, which are specific to each individual in most cases, therefore the establishment of a reliable method for neoantigen detection is essential for future clinical application. Regardless of the fact that binding affinity between a peptide and an HLA molecule is predictable, taking antigen processing selection mechanisms as well as cancer variations into account for in silico prediction is challenging.…”

Section: Neoantigensmentioning

confidence: 99%

Proteogenomic discovery of cancer antigens: Neoantigens and beyond

Kanaseki

Tokita

Torigoe

2019

Pathology International

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Host T cells infiltrate the cancer lesion and contribute to patient survival. T cells recognize antigen peptides displayed by the cancer cell human leukocyte antigen (HLA) system. Cancer antigens constitute an essential element of T‐cell discrimination and play an indispensable role in anti‐cancer responses. HLA ligandome analysis directly and comprehensively detects the peptides that are naturally presented by HLA of given cells, leading to discovery of cancer antigens. A proteogenomic approach, which combines conventional proteomics with genomic information, has further deciphered the landscape of the cancer HLA ligandome. Neoantigens that arise from somatic mutations are arguably the major type of peptides patient T cells recognize. Moreover, cancer cells present peptides derived from alleged noncoding regions, which also elicit T‐cell responses thereby serving as cancer antigens. The diversity of newly discovered antigen sources implies that T cells are capable of sensing a variety of genomic aberrations in cancer.

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Novel and shared neoantigen derived from histone 3 variant H3.3K27M mutation for glioma T cell therapy

Cited by 189 publications

References 58 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

CAR T cells for brain tumors: Lessons learned and road ahead

Proteogenomic discovery of cancer antigens: Neoantigens and beyond

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