Engineered T cells for cancer treatment

Anurathapan, Usanarat; Leen, Ann M.; Brenner, Malcolm K.; Vera, Juan F.

doi:10.1016/j.jcyt.2013.10.002

Cited by 20 publications

(12 citation statements)

References 223 publications

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“…If CAR-T cell-induced bystander effects are, in fact, quite limited, a second implication of our study is that, since most solid tumors do not express target antigen on >90% of tumor cells, other approaches will likely be needed for tumor eradication. A number of strategies are being explored that include: injection of a mixture of CAR T cells that target multiple tumor antigens; transducing T cells with multiple CARs targeting different antigens; 9 , 57 , 58 and designing CARs that target multiple antigens, 7 such as tandem CARs that express two linked single-chain variable fragments (scFvs) to recognize different antigens. 59 Another approach is to create CARs that also secrete payloads or cargos that are designed to kill tumor cells that are not expressing tumor antigens.…”

Section: Discussionmentioning

confidence: 99%

Analysis and Augmentation of the Immunologic Bystander Effects of CAR T Cell Therapy in a Syngeneic Mouse Cancer Model

Klampatsa

Leibowitz

Sun

et al. 2020

Molecular Therapy - Oncolytics

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The therapeutic efficacy of adoptive transfer of T cells transduced with chimeric antigen receptors (CARs) has been limited in the treatment of solid cancers, partly due to tumor antigen heterogeneity. Overcoming lack of universal tumor antigen expression would be achieved if CAR T cells could induce bystander effects. To study this process, we developed a system where CAR T cells targeting mesothelin could cure tumors containing 100% antigen-positive cells in immunocompetent mice. Using this model, we found that the CAR T cells were unable to cure tumors, even when only 10% of the tumor cells were mesothelin negative. A bystander effect was not induced by co-administration of anti-PD-1, anti-CTLA-4, or anti-TGF-β (transforming growth factor β) antibodies; agonistic CD40 antibodies; or an IDO (indoleamine 2,3-dioxygenase) inhibitor. However, pretreatment with a non-lymphodepleting dose of cyclophosphamide (CTX) prior to CAR T cells resulted in cures of tumors with up to 25% mesothelin-negative cells. The mechanism was dependent on endogenous CD8 T cells but not on basic leucine zipper transcription factor ATF-like 3 (BATF3)-dependent dendritic cells. These data suggest that CAR T cell therapy of solid tumors, in which the targeted antigen is not expressed by the vast majority of tumor cells, will not likely be successful unless combination strategies to enhance bystander effects are used.

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Section: Discussionmentioning

confidence: 99%

Analysis and Augmentation of the Immunologic Bystander Effects of CAR T Cell Therapy in a Syngeneic Mouse Cancer Model

Klampatsa

Leibowitz

Sun

et al. 2020

Molecular Therapy - Oncolytics

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“…T cells transfected with tumor‐specific conventional TCRs or with CARs have already been used successfully in clinical trials for adoptive therapy of several types of malignancies, for example in melanoma, myeloma and in haematologic malignancies . The majority of the patients showed a highly beneficial response, highlighting the therapeutic effectiveness of such therapies . However, as retroviral or lentiviral transduction was the method of choice to introduce the receptors into the effector T cells, the unintended reactivity or cross‐reactivity of the transgenic receptor, which occurred in some cases, resulted in long‐lasting severe auto‐aggression and on‐target, off‐tissue toxicity .…”

Section: Introductionmentioning

confidence: 99%

Combining a chimeric antigen receptor and a conventional T‐cell receptor to generate T cells expressing two additional receptors (TETARs) for a multi‐hit immunotherapy of melanoma

Uslu

Schuler

Dörrie

et al. 2016

Experimental Dermatology

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The adoptive transfer of engineered T cells represents an important approach in immunotherapy of melanoma. However, relapse of the tumor can occur due to immune-escape mechanisms developed by the tumor cells, for example antigen loss, downregulation of the major histocompatibility complex presentation machinery and defects in antigen processing. To counteract these mechanisms, we combined a T-cell receptor and a chimeric antigen receptor, specific for different common melanoma antigens, gp100 (PMEL) and MCSP (HMW-MAA), to generate functional CD8 T cells expressing two additional receptors (TETARs) by electroporation of receptor-encoding mRNA. These TETARs produced cytokines and were lytic upon recognition of each of their cognate antigens, while no reciprocal inhibition of the receptors occurred. When stimulated with target cells, which express both antigens, an enhanced effect was suggested. The confirmation that chimeric antigen receptors and T-cell receptors can be functionally combined opens up new avenues in cancer immunotherapy, and the generation of TETARs helps by-passing major mechanisms by which tumor cells escape immune recognition.

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“…In the vast majority of clinical studies, immunogenicity of the receptor has not been recognized as a possible limitation, most likely due to the applied non-myoablative preconditioning of patients in most studies, single T-cell infusions and a recent dominance of CD19 CAR T-cell studies [52,53]. Yet, our study clearly demonstrated the immunogenicity of xenogeneic protein sequences presented by T-cells [41].…”

Section: Recommendationsmentioning

confidence: 72%

“…To date, it has been shown that T-cell persistence and therapy efficiency improves from modification of the receptor design, in particular, by including a costimulatory domain in the receptor [52,53]. In addition, T-cells armoured with features that can adapt the immunesuppressive tumour microenvironment, e.g.…”

Section: Recommendationsmentioning

confidence: 99%

Treatment of metastatic renal cell carcinoma (mRCC) with CAIX CAR-engineered T-cells–a completed study overview

Lamers

Klaver

Gratama

et al. 2016

Biochemical Society Transactions

132

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We studied safety and proof of concept of a phase I/II trial with chimeric antigen receptor (CAR) T-cells in patients with metastatic renal cell carcinoma (mRCC). The CAR was based on the G250 mAb that recognized an epitope of carboxy-anhydrase-IX (CAIX). Twelve patients with CAIX+ mRCC were treated in three cohorts with a maximum of 10 daily infusions of 2×10(7) to 2×10(9) CAR T-cells. Circulating CAR T-cells were transiently detectable in all patients and maintained antigen-specific immune functions following their isolation post-treatment. Blood cytokine profiles mirrored CAR T-cell presence and in vivo activity. Unfortunately, patients developed anti-CAR T-cell antibodies and cellular immune responses. Moreover, CAR T-cell infusions induced liver enzyme disturbances reaching CTC grades 2-4, which necessitated cessation of treatment in four out of eight patients (cohort 1+2). Examination of liver biopsies revealed T-cell infiltration around bile ducts and CAIX expression on bile duct epithelium, adding to the notion of on-target toxicity. No such toxicities were observed in four patients that were pretreated with G250 mAb (cohort 3). The study was stopped due to the advent of competing treatments before reaching therapeutic or maximum tolerated dose in cohort 3. No clinical responses have been recorded. Despite that, from this trial numerous recommendations for future trials and their immune monitoring could be formulated, such as choice of the target antigen, format and immunogenicity of receptor and how the latter relates to peripheral T-cell persistence.

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Engineered T cells for cancer treatment

Cited by 20 publications

References 223 publications

Analysis and Augmentation of the Immunologic Bystander Effects of CAR T Cell Therapy in a Syngeneic Mouse Cancer Model

Analysis and Augmentation of the Immunologic Bystander Effects of CAR T Cell Therapy in a Syngeneic Mouse Cancer Model

Combining a chimeric antigen receptor and a conventional T‐cell receptor to generate T cells expressing two additional receptors (TETARs) for a multi‐hit immunotherapy of melanoma

Treatment of metastatic renal cell carcinoma (mRCC) with CAIX CAR-engineered T-cells–a completed study overview

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