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Efficacy-enhanced anti-CD7 universal chimeric antigen receptor-T cell therapy for relapsed/refractory CD7-positive hematological malignancies: A phase I clinical study

ABSTRACT: Chimeric antigen receptor-T cell (CAR-T) therapy in T cell malignancies faces fratricide, T cell aplasia, and product contamination. We developed an universal anti-CD7 CAR-T cells in which TRAC, CD7 and HLA-II were disrupted, while E-cadherin (a NK cell inhibitory molecule) was introduced, to mitigate graft versus host disease (GvHD), fratricide and rejection. Furthermore, we designed a subtle receptor, bbzg-CAR, comprising not only conventional domains (anti-CD7 scFv, 4-1BB co-stimulatory domain, and CD3ζ signaling domain), but also the intracellular domain of common γ chain. Bbzg-CAR-T exerted anti-tumor effects superior to those of conventional universal CAR-T cells. In adoptive therapy for relapsed/refractory (r/r) patients, no dose-limiting toxicity, GvHD, immune effector cell-associated neurotoxicity or severe cytokine release syndrome (grade≥3) was observed. Nine patients (82%) showed objective response with, complete response rates of 75% and 33.3% in r/r leukemia and lymphoma respectively. Preliminary safety and efficacy of this universal CAR-T product was achieved in CD7+ malignancies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE192453 | GEO | 2022/09/08

REPOSITORIES: GEO

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Project description:This model of the use of chimeric antigen receptor (CAR)-T cell therapy in the treatment of solid tumours is described in the article: "Dual-Target CAR-Ts with On- and Off-Tumour Activity May Override Immune Suppression in Solid Cancers: A Mathematical Proof of Concept" Odelaisy León-Triana, Antonio Pérez-Martínez, Manuel Ramírez-Orellana and Víctor M. Pérez-García Cancers 2021, 13, 703.; doi: 10.3390/cancers13040703 Comment: This is the first mathematical model, derived from equations 1 and 2, used in the paper. Reproduction of Fig. 5a was achieved by setting alpha_1 = 0.04, different to the value quoted in the article caption for Fig. 5. Abstract: Chimeric antigen receptor (CAR)-T cell-based therapies have achieved substantial success against B-cell malignancies, which has led to a growing scientific and clinical interest in extending their use to solid cancers. However, results for solid tumours have been limited up to now, in part due to the immunosuppressive tumour microenvironment, which is able to inactivate CAR-T cell clones. In this paper we put forward a mathematical model describing the competition of CAR-T and tumour cells, taking into account their immunosuppressive capacity. Using the mathematical model, we show that the use of large numbers of CAR-T cells targetting the solid tumour antigens could overcome the immunosuppressive potential of cancer. To achieve such high levels of CAR-T cells we propose, and study computationally, the manufacture and injection of CAR-T cells targetting two antigens: CD19 and a tumour-associated antigen. We study in silico the resulting dynamics of the disease after the injection of this product and find that the expansion of the CAR-T cell population in the blood and lymphopoietic organs could lead to the massive production of an army of CAR-T cells targetting the solid tumour, and potentially overcoming its immune suppression capabilities. This strategy could benefit from the combination with PD-1 inhibitors and low tumour loads. Our computational results provide theoretical support for the treatment of different types of solid tumours using T cells engineered with combination treatments of dual CARs with on- and off-tumour activity and anti-PD-1 drugs after completion of classical cytoreductive treatments.

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Efficacy-enhanced anti-CD7 universal chimeric antigen receptor-T cell therapy for relapsed/refractory CD7-positive hematological malignancies: A phase I clinical study

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