Gene-modified T cells as immunotherapy for multiple myeloma and acute myeloid leukemia expressing the Lewis Y antigen

Peinert, Stefan; Prince, H. Miles; Guru, P; Kershaw, Michael H.; Smyth, Mark J.; Trapani, Joseph A.; Gambell, Peter; Harrison, Simon J.; Scott, Andrew M.; Smyth, Fiona E; Darcy, Phillip K.; Tainton, Kellie M.; Neeson, Paul J.; Ritchie, David; Hönemann, Dirk

doi:10.1038/gt.2010.21

Cited by 101 publications

(67 citation statements)

References 36 publications

(38 reference statements)

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“…[35][36][37] Although the interleukin-6 receptor antagonist tocilizumab appears to reduce cytokine release syndrome 38 it would still be desirable to minimize the occurrence of such severe side effects. Furthermore, since we cannot rule out toxicities occurring due to the possible attack of nonhematopoietic CD38 + cells, development of an optimal CD38-CART-cell therapy would require the improvement of the target-specificity as well as the in vivo control of CD38-CART cells, and probably also in the case of other CART-cell approaches targeting the kappa light chain, 39 CD138, 40 Lewis Y antigen, 41 BCMA, 42 CS1, 43,44 and CD44v6. 45 One future option to improve the target-specificity could be optimization of the target cell affinity of CART cells.…”

Section: A B C Dmentioning

confidence: 99%

Pre-clinical evaluation of CD38 chimeric antigen receptor engineered T cells for the treatment of multiple myeloma

et al. 2016

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A doptive transfer of chimeric antigen receptor-transduced T cells is a promising strategy for cancer immunotherapy. The CD38 molecule, with its high expression on multiple myeloma cells, appears a suitable target for antibody therapy. Prompted by this, we used three different CD38 antibody sequences to generate second-generation retroviral CD38-chimeric antigen receptor constructs with which we transduced T cells from healthy donors and multiple myeloma patients. We then evaluated the preclinical efficacy and safety of the transduced T cells. Irrespective of the donor and antibody sequence, CD38-chimeric antigen receptor-transduced T cells proliferated, produced inflammatory cytokines and effectively lysed malignant cell lines and primary malignant cells from patients with acute myeloid leukemia and multi-drug resistant multiple myeloma in a cell-dose, and CD38-dependent manner, despite becoming CD38-negative during culture. CD38-chimeric antigen receptor-transduced T cells also displayed significant anti-tumor effects in a xenotransplant model, in which multiple myeloma tumors were grown in a human bone marrow-like microenvironment. CD38-chimeric antigen receptor-transduced T cells also appeared to lyse the CD38 + fractions of CD34 + hematopoietic progenitor cells, monocytes, natural killer cells, and to a lesser extent T and B cells but did not inhibit the outgrowth of progenitor cells into various myeloid lineages and, furthermore, were effectively controllable with a caspase-9-based suicide gene. These results signify the potential importance of CD38-chimeric antigen receptor-transduced T cells as therapeutic tools for CD38 + malignancies and warrant further efforts to diminish the undesired effects of this immunotherapy using appropriate strategies. Pre-clinical evaluation of CD38 chimeric antigen receptor engineered T cells for the treatment of multiple myeloma

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Section: A B C Dmentioning

confidence: 99%

Pre-clinical evaluation of CD38 chimeric antigen receptor engineered T cells for the treatment of multiple myeloma

et al. 2016

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“…This CAR approach is now being explored in myeloma, with a number of potential targets identified, including CD138, CD38, CD44v, kappa light chain, Lewis Y, CS1/SLAMF7 and BCMA. Preclinical studies have shown that T cells or in some cases, NK cells expressing CARs specific for these targets can kill myeloma cells in vitro and in xenograft models, [86][87][88][89][90][91] and several have now entered early-phase clinical trials. One target of interest is B-cell maturation Ag (BCMA).…”

Section: Car 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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“…[11][12][13][14][15] In contrast, CAR-engineered T cells for the treatment of AML remain scarce. [16][17][18] Here, we describe the generation of 2 novel CD123-targeting CARs using scFvs from previously described recombinant immunotoxins, 26292 and 32716, which bind distinct epitopes and have similar binding affinities for CD123. 19 We hypothesized that T cells expressing CARs derived from either 26292 or 32716 would effectively redirect T-cell specificity against CD123-expressing cells.…”

Section: Introductionmentioning

confidence: 99%

T cells expressing CD123-specific chimeric antigen receptors exhibit specific cytolytic effector functions and antitumor effects against human acute myeloid leukemia

Mardiros¹,

Santos²,

McDonald³

et al. 2013

Blood

320

236

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Gene-modified T cells as immunotherapy for multiple myeloma and acute myeloid leukemia expressing the Lewis Y antigen

Cited by 101 publications

References 36 publications

Pre-clinical evaluation of CD38 chimeric antigen receptor engineered T cells for the treatment of multiple myeloma

Pre-clinical evaluation of CD38 chimeric antigen receptor engineered T cells for the treatment of multiple myeloma

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

T cells expressing CD123-specific chimeric antigen receptors exhibit specific cytolytic effector functions and antitumor effects against human acute myeloid leukemia

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