On November 3, 2023 Allogene Therapeutics, Inc. (Nasdaq: ALLO), a clinical-stage biotechnology company pioneering the development of allogeneic CAR T (AlloCAR T) products for cancer, reported data highlighting the Company’s next generation Cloak and Dagger technologies designed to help enhance engraftment, expansion and the persistence of AlloCAR T cell candidates, at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting November 1-5, 2023, in San Diego, CA (Press release, Allogene, NOV 3, 2023, View Source [SID1234636877]).
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The development of "off-the-shelf" CAR T products that utilize cells from healthy donors has the potential to make CAR T therapies scalable and accessible to more patients. However, the effectiveness of allogeneic CAR T cells requires controlling rejection of the allogeneic CAR T cells by the patient’s immune system. Allogene’s proprietary Cloak and Dagger technologies are two novel strategies the Company is investigating to help control immune rejection and enhance expansion, persistence, and performance of AlloCAR T cells with the use of standard lymphodepletion regimens.
"These promising data show that both our Cloak and Dagger technology platforms can engineer AlloCAR T cells to minimize the potential of rejection by host immune cells, without impacting performance and in some cases, enhancing efficacy," said Zachary Roberts, M.D., Ph.D., Executive Vice President, Research & Development and Chief Medical Officer of Allogene. "These innovative approaches are intended to simplify the lymphodepletion requirement for allogeneic CAR T products, and may provide a path to further expand the potential of off-the-shelf CAR T products beyond current targets and indications."
The Cloak platform technology is designed to prevent AlloCAR T cells from being recognized by host T cells without triggering substantial natural killer (NK) cell rejection while preserving CAR T cell function. Data shown previously demonstrated that knockout of RFX5, a transcriptional regulator that controls expression of HLA molecules, enhanced survival of allogeneic CAR T cells in the presence of host T cells and elicited only minor NK cell reactivity, thereby effectively mitigating rejection.
This preclinical study evaluated an additional anti-rejection approach to immune evasion by inactivating CD58 and ICAM-1, key components of the immune synapse required for effective recognition and lysis by alloreactive T/NK cells. In the study, the survival of "cloaked" cells was assessed in mixed lymphocyte reaction assays with T cells and NK cells. The knockout of CD58 and ICAM-1 effectively reduced T cell rejection of allogeneic CAR T cells without triggering NK cell rejection or impacting effector function and worked additively with the knockout of RFX5.
The Dagger platform technology arms AlloCAR T cells with a CD70 CAR designed to recognize and deplete CD70-positive host immune cells while enabling tumor-targeting anti-CD19 AlloCAR T cells to resist rejection from the host immune cells. This endows the CAR-expressing T cells with dual specificity against tumors that co-express CD19 and CD70, which includes approximately 70% of patients with large B-cell lymphoma (LBCL). As a result, this potential advance provides both a prolonged window of persistence during which AlloCAR T cells can expand and actively target and destroy cancer cells as well as insure against CD19 loss-mediated tumor escape, a known mechanism of resistance to CD19 CAR T therapy.
The Dagger technology, a feature of our ALLO-316 candidate, has clinically demonstrated its unique immunomodulatory effect, contributing to robust AlloCAR T cell expansion and persistence even with relatively lower doses of CAR T cells and lymphodepletion than in other AlloCAR T programs. The ongoing Phase 1 dose escalation TRAVERSE study using investigational ALLO-316 in patients with advanced or metastatic renal cell carcinoma (RCC) who have progressed on standard therapies including an immune checkpoint inhibitor and a VEGF-targeting therapy.