Preclinical targeting of human T-cell malignancies using CD4-specific chimeric antigen receptor (CAR)-engineered T cells

Pinz, Kevin G.; Liu, H; Golightly, Marc G.; Jares, Alexander; Lan, Fengshuo; Zieve, Gary W.; Hagag, Nabil; Schuster, Manfred; Firor, Amelia E.; Jiang, Xun; Ma, Yupo

doi:10.1038/leu.2015.311

Cited by 96 publications

(65 citation statements)

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“…Certain cell surface antigens such as CD5 (6) have been targeted using specific CARs, and downregulation of their expression in activated T cells has allowed effector cells to expand and yield a product. Similarly, CD4 has been targeted by CD8 + T cells expressing a CD4-specific CAR (7), and CARs discriminating between T cell receptor constant regions (TRBC1 or TRBC2) have also been developed, with the aim of eradicating whichever of the 2 compartments malignant transformation may have arisen in (8). In addition, CRIS-PR/Cas9-mediated disruption of CD7 expression has also recently been reported in T cells transduced to express a CD7-specific CAR (9), as well as alternative strategies deploying an anti-CD7 scFv linked to T cells engineered to express chimeric antigen receptors (CARs) against B cell antigens are being investigated as cellular immunotherapies.…”

Section: Introductionmentioning

confidence: 99%

TCRαβ/CD3 disruption enables CD3-specific antileukemic T cell immunotherapy

et al. 2018

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T cells engineered to express chimeric antigen receptors (CARs) against B cell antigens are being investigated as cellular immunotherapies. Similar approaches designed to target T cell malignancies have been hampered by the critical issue of T-on-T cytotoxicity, whereby fratricide or self-destruction of healthy T cells prohibits cell product manufacture. To date, there have been no reports of T cells engineered to target the definitive T cell marker, CD3 (3CAR). Recent improvements in gene editing now provide access to efficient disruption of such molecules on T cells, and this has provided a route to generation of 3CAR, CD3-specific CAR T cells. T cells were transduced with a lentiviral vector incorporating an anti-CD3ε CAR derived from OKT3, either before or after TALEN-mediated disruption of the endogenous TCRαβ/CD3 complex. Only transduction after disrupting assembly of TCRαβ/CD3 yielded viable 3CAR T cells, and these cultures were found to undergo self-enrichment for 3CAR+TCR-CD3- T cells without any further processing. Specific cytotoxicity against CD3ε was demonstrated against primary T cells and against childhood T cell acute lymphoblastic leukemia (T-ALL). 3CAR T cells mediated potent antileukemic effects in a human/murine chimeric model, supporting the application of cellular immunotherapy strategies against T cell malignancies. 3CAR provides a bridging strategy to achieve T cell eradication and leukemic remission ahead of conditioned allogeneic stem cell transplantation.

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Section: Introductionmentioning

confidence: 99%

TCRαβ/CD3 disruption enables CD3-specific antileukemic T cell immunotherapy

et al. 2018

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“…Treatment of B-cell malignancies with anti-CD19 CART-cells has been one of the most important recent advances in the treatment of cancer, with sustainedremissions obtained in most patients with advanced and refractory B-ALL6,32 , as well as impressive though lesser responses in CLL7,33 and diffuse large B-cell lymphoma 7 .Given the relatively similar presentation and nature of B-and T-cell malignancies,CART-cells could potentially have similar value in treating T-cell lymphomas.However, anti-CD19 CART efficacy is accompanied by loss of the normal B-cell compartment6,7 . While this is relatively well tolerated, and impact can be lessened by infusion of donor-derived pooled immunoglobulins, analogously targeting a pan-T-cell antigen on a T-cell malignancy (with concomitant permanent loss of normal T-cells) would be prohibitively toxic, with no mitigating replacement therapies available.Approaches using CARs against T-cell targets such as the pan T-cell antigen CD534 or CD4, which is present on a crucial subset of normal T-cells35 , have been proposed, but may prove unacceptably immunosuppressive in clinical use. With our approach, a patient treated with anti-TRBC1 CART would retain approximately 2/3 of normal Tcells, with polyclonal anti-viral immunity likely preserved.…”

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confidence: 99%

Targeting the T cell receptor β-chain constant region for immunotherapy of T cell malignancies

Maciocia¹,

Wawrzyniecka²,

Philip³

et al. 2017

Nat Med

222

187

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Mature T cell cancers are typically aggressive, treatment resistant and associated with poor prognosis. Clinical application of immunotherapeutic approaches has been limited by a lack of target antigens that discriminate malignant from healthy (normal) T cells. Unlike B cell depletion, pan-T cell aplasia is prohibitively toxic. We report a new targeting strategy based on the mutually exclusive expression of T cell receptor β-chain constant domains 1 and 2 (TRBC1 and TRBC2). We identify an antibody with unique TRBC1 specificity and use it to demonstrate that normal and virus-specific T cell populations contain both TRBC1 and TRBC2 compartments, whereas malignancies are restricted to only one. As proof of concept for anti-TRBC immunotherapy, we developed anti-TRBC1 chimeric antigen receptor (CAR) T cells, which recognized and killed normal and malignant TRBC1, but not TRBC2, T cells in vitro and in a disseminated mouse model of leukemia. Unlike nonselective approaches targeting the entire T cell population, TRBC-targeted immunotherapy could eradicate a T cell malignancy while preserving sufficient normal T cells to maintain cellular immunity.

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“…The development of new conditioning regimens and the use of alternate alloHCT donors [28][29][30] provides NHL patients eligible for alloHCT with more treatment options not limited by their age. The data from this retrospective study are even more relevant now with the availability of treatment with autologous chimeric antigen receptor (CAR) T cells [31][32][33][34][35][36][37][38][39] and donor-derived CAR T [40][41][42] or the administration of CAR T cells after relapse post-alloHCT [39,[43][44][45].…”

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confidence: 99%

The Impact of Advanced Patient Age on Mortality after Allogeneic Hematopoietic Cell Transplantation for Non-Hodgkin Lymphoma: A Retrospective Study by the European Society for Blood and Marrow Transplantation Lymphoma Working Party

Kyriakou

Boumendil

Finel

et al. 2019

Biology of Blood and Marrow Transplantation

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More than 60% of patients with non-Hodgkin lymphoma (NHL) are age >60 years at presentation. The purpose of this study was to compare the potential risks and benefits of allogeneic hematopoietic cell transplantation (alloHCT) in elderly patients with NHL with younger patients in a large sample, also taking into account comorbidity information. All patients age ≥18 years who had undergone alloHCT from a matched sibling or unrelated donor for NHL between 2003 and 2013 and were registered with the European Society for Blood and Marrow Transplantation were eligible for the study. The primary study endpoint was 1-year nonrelapse mortality (NRM). A total of 3919 patients were eligible and were categorized by age: young (Y), 18 to 50 y (n = 1772); middle age (MA), 51 to 65 y (n = 1967); or old (O), 66 to 77 y (n = 180). Follicular lymphoma was present in 37% of the patients; diffuse large B cell lymphoma, in 30%; mantle cell lymphoma, in 21%, and peripheral T cell lymphoma, in 11%. At the time of alloHCT, 85% of the patients were chemosensitive and 15% were chemorefractory. With a median follow-up of 4.5 years in survivors, NRM at 1 year was 13% for the Y group. 20% for the MA group, and 33% for the O group (P <.001), whereas relapse incidence and overall survival (OS) at 3 years in the 3 groups were 30%, 31%, and 28% (P = .355) and 60%, 54%, and 38% (P <.001), respectively. Multivariable adjustment for confounders, including sex, NHL subset, time from diagnosis, chemosensitivity, donor, and conditioning, confirmed older age as a significant predictor for NRM and OS, but not for relapse risk. Although comorbidity was a significant predictor of NRM in a subset analysis restricted to the 979 patients with comorbidity information available, age retained its significant impact on NRM. In conclusion, our data show that alloHCT in patients age >65 y provides similar NHL control as seen in younger patients but is associated with a higher NRM that is not fully explained by comorbidity. Thus, although alloHCT is feasible and effective in very old patients, the increased NRM risk must be taken into account when assessing the indication for alloHCT for NHL in this age group.

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Preclinical targeting of human T-cell malignancies using CD4-specific chimeric antigen receptor (CAR)-engineered T cells

Cited by 96 publications

References 50 publications

TCRαβ/CD3 disruption enables CD3-specific antileukemic T cell immunotherapy

TCRαβ/CD3 disruption enables CD3-specific antileukemic T cell immunotherapy

Targeting the T cell receptor β-chain constant region for immunotherapy of T cell malignancies

The Impact of Advanced Patient Age on Mortality after Allogeneic Hematopoietic Cell Transplantation for Non-Hodgkin Lymphoma: A Retrospective Study by the European Society for Blood and Marrow Transplantation Lymphoma Working Party

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