Novel TCR-like CAR-T cells targeting an HLA∗0201-restricted SSX2 epitope display strong activity against acute myeloid leukemia

Raskin, Scott; Pelt, Stacey Van; Toner, Keri; Balakrishnan, Preethi Bala; Dave, Hema; Bollard, Catherine M.; Yvon, Eric

doi:10.1016/j.omtm.2021.09.008

Cited by 18 publications

(14 citation statements)

References 41 publications

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“…Another alternative is development of TCR-like CAR T-cells which are made from a scFv and CAR signaling machinery, but are instead generated to recognize peptide in the context of MHC class I molecules [54]. TCR CAR T-cells have successfully targeted intracellular synovial sarcoma X breakpoint 2 (SSX2) in the context of HLA*0201 as well as mutated nucleophosmin (NPM1) in the context of HLA-A2 in AML cancer cell lines [55,56]. Xenograft models using TCR CAR T-cells generated against the Wilms' Tumor Antigen-1 (WT1)/HLA*2402 complex were additionally enhanced by dendritic cell vaccination [57].…”

Section: Lack Of Aml-specific Antigensmentioning

confidence: 99%

Challenges and Advances in Chimeric Antigen Receptor Therapy for Acute Myeloid Leukemia

Marvin-Peek

Savani

Oluwole

et al. 2022

Cancers

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The advent of chimeric antigen receptor (CAR) T-cell therapy has led to dramatic remission rates in multiple relapsed/refractory hematologic malignancies. While CAR T-cell therapy has been particularly successful as a treatment for B-cell malignancies, effectively treating acute myeloid leukemia (AML) with CARs has posed a larger challenge. AML not only creates an immunosuppressive tumor microenvironment that dampens CAR T-cell responses, but it also lacks many unique tumor-associated antigens, making leukemic-specific targeting difficult. One advantage of CAR T-cell therapy compared to alternative treatment options is the ability to provide prolonged antigen-specific immune effector and surveillance functions. Since many AML CAR targets under investigation including CD33, CD117, and CD123 are also expressed on hematopoietic stem cells, CAR T-cell therapy can lead to severe and potentially lethal myeloablation. Novel strategies to combat these issues include creation of bispecific CARs, CAR T-cell “safety switches”, TCR-like CARs, NK CARs, and universal CARs, but all vary in their ability to provide a sustained remission, and consolidation with an allogeneic hematopoietic cell transplantation (allo-HCT) will be necessary in most cases This review highlights the delicate balance between effectively eliminating AML blasts and leukemic stem cells, while preserving the ability for bone marrow to regenerate. The impact of CAR therapy on treatment landscape of AML and changing scope of allo-HCT is discussed. Continued advances in AML CAR therapy would be of great benefit to a disease that still has high morbidity and mortality.

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Section: Lack Of Aml-specific Antigensmentioning

confidence: 99%

Challenges and Advances in Chimeric Antigen Receptor Therapy for Acute Myeloid Leukemia

Marvin-Peek

Savani

Oluwole

et al. 2022

Cancers

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“…Its principle is to combine an extracellular single chain variable fragment (scFv) that recognize the WT1 peptide-human leukocyte antigens (HLA) complex (as a full TCR do) with other CAR elements to generate TCR-like CAR-T cells ( 16 , 17 ). Besides WT1, other intracellular antigen peptide-HLA complexes for CAR-T cell therapy have been investigated, including NY-ESO-1/HLA-A2 for potentially MM ( 18 ), HA-1H (derived from minor histocompatibility antigen 1, HMHA1)/HLA-A2 for chronic myelogenous leukemia ( 19 ), and SSX2/HLA∗0201 for acute myeloid leukemia (AML) ( 20 ). However, one of the difficulties of TCR-like CAR is that the target peptide and its associated HLA allele vary in different patients and cancers (e.g., WT1 235-243 /HLA-A*2402 ( 16 ) or WT1 126-134 /HLA-A*02:01 ( 17 )).…”

Section: Target Exploration and Strategies To Overcome Antigen Loss A...mentioning

confidence: 99%

CAR-T cell therapy for hematological malignancies: Limitations and optimization strategies

Huang

2022

Front. Immunol.

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In the past decade, the emergence of chimeric antigen receptor (CAR) T-cell therapy has led to a cellular immunotherapy revolution against various cancers. Although CAR-T cell therapies have demonstrated remarkable efficacy for patients with certain B cell driven hematological malignancies, further studies are required to broaden the use of CAR-T cell therapy against other hematological malignancies. Moreover, treatment failure still occurs for a significant proportion of patients. CAR antigen loss on cancer cells is one of the most common reasons for cancer relapse. Additionally, immune evasion can arise due to the hostile immunosuppressive tumor microenvironment and the impaired CAR-T cells in vivo persistence. Other than direct antitumor activity, the adverse effects associated with CAR-T cell therapy are another major concern during treatment. As a newly emerged treatment approach, numerous novel preclinical studies have proposed different strategies to enhance the efficacy and attenuate CAR-T cell associated toxicity in recent years. The major obstacles that impede promising outcomes for patients with hematological malignancies during CAR-T cell therapy have been reviewed herein, along with recent advancements being made to surmount them.

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“…The expression of cancer testis antigen is very low in normal tissues, and the probability of off-target effects is low. It is an ideal target antigen for adoptive cellular immunotherapy [ 79 ]. NY-ESO-1 TCR-T therapy was used in 20 patients with multiple myeloma, the clinical response rate was 80%, and TCR was continuously expressed in vivo for more than two years [ 21 ].…”

Section: Application Of Targeted Kk-lc-1 In Tumor Immunotherapymentioning

confidence: 99%

Kita-Kyushu Lung Cancer Antigen-1 (KK-LC-1): A Promising Cancer Testis Antigen

Bai¹,

Cheng²

2022

Aging and disease

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Cancer has always been a huge problem in the field of human health, and its early diagnosis and treatment are the key to solving this problem. Cancer testis antigens (CTAs) are a family of multifunctional proteins that are specifically expressed in male spermatozoa and tumor cells but not in healthy somatic cells. Studies have found that CTAs are involved in the occurrence and development of tumors, and some CTAs trigger immunogenicity, which suggests a possibility of tumor immunotherapy. The differential expression and function of CTAs in normal tissues and tumor cells can promote the screening of tumor markers and the development of new immunotherapies. This article introduces the expression of Kita-Kyushu lung cancer antigen-1 (KK-LC-1), a new member of the CTA family, in different types of tumors and its role in immunotherapy.

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Novel TCR-like CAR-T cells targeting an HLA∗0201-restricted SSX2 epitope display strong activity against acute myeloid leukemia

Cited by 18 publications

References 41 publications

Challenges and Advances in Chimeric Antigen Receptor Therapy for Acute Myeloid Leukemia

Challenges and Advances in Chimeric Antigen Receptor Therapy for Acute Myeloid Leukemia

CAR-T cell therapy for hematological malignancies: Limitations and optimization strategies

Kita-Kyushu Lung Cancer Antigen-1 (KK-LC-1): A Promising Cancer Testis Antigen

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