Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma

Linette, Gerald P.; Stadtmauer, Edward A.; Maus, Marcela V.; Rapoport, Aaron P.; Levine, Bruce L.; Emery, Lyndsey; Litzky, Leslie A.; Bagg, Adam; Carreño, Beatriz M.; Cimino, Patrick J.; Binder-Scholl, Gwendolyn; Smethurst, Dominic; Gerry, Andrew B.; Pumphrey, Nick; Bennett, Alan; Brewer, Joanna E.; Dukes, Joseph; Harper, Jane; Tayton-Martin, Helen K.; Jakobsen, Bent K.; Hassan, Namir J.; Kalos, Michael; June, Carl H.

doi:10.1182/blood-2013-03-490565

Cited by 935 publications

(845 citation statements)

References 30 publications

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“…Subsequent studies demonstrated that the Tg TCR also recognized an epitope from titin, a cardiac myocyte protein, leading to massive cardiac T-cell infiltration and cardiomyocyte necrosis. 80 Thus, very careful selection of potential peptide targets, with extensive in silico and in vitro testing for cross-reactivity to normal tissue epitopes, is necessary for this approach.…”

Section: Tcr Transgenic T Cellsmentioning

confidence: 99%

Beyond consolidation: auto-SCT and immunotherapy for plasma cell myeloma

Lendvai

Cohen

Cho

2015

Bone Marrow Transplant

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Autologous hematopoietic cell transplantation (auto-HCT) is the standard consolidation therapy for plasma cell myeloma patients following induction therapy. Auto-HCT improves disease-free survival (DFS), but is generally not curative. The allogeneic HCT experience demonstrated that T-cell immunotherapy can confer long-term DFS. Preclinical and clinical data indicate that myelomaassociated Ags elicit humoral and cellular immune responses (IRs) in myeloma patients. These findings strongly suggest that the immunotherapeutic strategies, including immune checkpoint inhibitors, therapeutic cancer vaccines and adoptive cellular therapies, are promising avenues of clinical research that may be most applicable in the minimal residual disease state following auto-HCT. These strategies are designed to prime or augment antimyeloma IRs and promote a 'host-vs-myeloma' effect that may result in durable DFS. Innovative clinical trials investigating immune checkpoint inhibitors and cancer vaccines have demonstrated that robust immunity against myeloma-associated Ags can be elicited in the setting of auto-HCT. A diverse array of immunotherapeutic strategies have entered clinical trials in myeloma, including PD-1/PD-L1 inhibitors, DC/myeloma cell fusion vaccines and adoptive chimeric Ag receptor T-cell therapy, and further investigation of combinations of immunologic and pharmaceutical agents are expected in the near future. In this review, we will discuss the preclinical data supporting immunotherapy in auto-HCT for myeloma, clinical investigation of these strategies and the future prospects of immunotherapy in pursuit of the goal of curative therapy.

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Section: Tcr Transgenic T Cellsmentioning

confidence: 99%

Beyond consolidation: auto-SCT and immunotherapy for plasma cell myeloma

Lendvai

Cohen

Cho

2015

Bone Marrow Transplant

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“…Only the use of highly purified human cardiomyocytes derived from induced pluripotent stem cells revealed the reactivity with the titin peptide expressed in beating cardiac myocytes. 34 Despite advances in modern technology, the ability for pre-clinical models to detect the cross-reactivity of various TCR constructs remains challenging, and no standardized tests or assays can reliably predict all potential off-target toxicities.…”

Section: Off-target Toxicitiesmentioning

confidence: 99%

The Flipside of the Power of Engineered T Cells: Observed and Potential Toxicities of Genetically Modified T Cells as Therapy

2017

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“…For instance, in a study using high-affinity HLA-A*01-restricted MAGE-A3 TCRs in myeloma and melanoma patients, one group reported fatal cardiogenic shock within days of infusion in 2 patients. (Linette et al 2013) In addition to marked increase in serum cytokines correlating with robust T-cell expansion, autopsy reports revealed severe myocardial damage with T-cell infiltration of the myocardium. Notably, MAGE-A3 was not detected in myocardial autopsy tissue, but additional studies led to the conclusion that the engineered T-cells recognized a similar peptide epitope derived from unrelated striated muscle protein (titin) expressed in beating cardiomyocytes.…”

Section: Genetic Transfer Of Exogenous Tcrsmentioning

confidence: 99%

Recent advances in T‐cell immunotherapy for haematological malignancies

et al. 2016

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In vitro discoveries have paved the way for bench-to-bedside translation in adoptive T cell immunotherapy, resulting in remarkable clinical responses in a variety of haematological malignancies. Adoptively transferred T cells genetically modified to express CD19 CARs have shown great promise, although many unanswered questions regarding how to optimize T-cell therapies for both safety and efficacy remain. Similarly, T cells that recognize viral or tumour antigens though their native receptors have produced encouraging clinical responses. Honing manufacturing processes will increase the availability of T-cell products, while combining T-cell therapies has the ability to increase complete response rates. Lastly, innovative mechanisms to control these therapies may improve safety profiles while genome editing offers the prospect of modulating T-cell function. This review will focus on recent advances in T-cell immunotherapy, highlighting both clinical and pre-clinical advances, as well as exploring what the future holds.

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Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma

Abstract: Key Points Engineered T-cell receptors can have redundant recognition of alternative protein motifs, resulting in severe cardiac toxicity. The use of induced pleuripotent stem cells (iPSCs) is a promising approach to identify potential off-target effects of engineered T cells.

Cited by 935 publications

References 30 publications

Beyond consolidation: auto-SCT and immunotherapy for plasma cell myeloma

Beyond consolidation: auto-SCT and immunotherapy for plasma cell myeloma

The Flipside of the Power of Engineered T Cells: Observed and Potential Toxicities of Genetically Modified T Cells as Therapy

Recent advances in T‐cell immunotherapy for haematological malignancies

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