作者: Wang, Xuefeng ; Lynch, Conor C. ; Snedal, Sebastian A. ; de la Iglesia, Janis ; Cianne, E. Junior ; Roselli, Emiliano ; Benzaid, Ismahene ; Abate-Daga, Daniel ; Lo, Chen Hao ; Kim, Youngchul ; Bustos, Xiomar E. ; Tordesillas, Leticia ; Frieling, Jeremy S. ; Li, Tao ; Bishop, Ryan T. ; Ramello, Maria Cecilia

Immune checkpoint blockade has been largely unsuccessful for the treatment of bone metastatic castrate-resistant prostate cancer (mCRPC). Here, we report a combinatorial strategy to treat mCRPC using γδ-enriched chimeric antigen receptor (CAR) T cells and zoledronate (ZOL). In a preclinical murine model of bone mCRPC, γδ CAR-T cells targeting prostate stem cell antigen (PSCA) induced a rapid and significant regression of established tumors, combined with increased survival and reduced cancer-associated bone disease. Pretreatment with ZOL, a U.S. Food and Drug Administration–approved bisphosphonate prescribed to mitigate pathological fracture in mCRPC patients, resulted in CAR-independent activation of γδ CAR-T cells, increased cytokine secretion, and enhanced antitumor efficacy. These data show that the activity of the endogenous Vγ9Vδ2 T cell receptor is preserved in CAR-T cells, allowing for dual-receptor recognition of tumor cells. Collectively, our findings support the use of γδ CAR-T cell therapy for mCRPC treatment.

2023-02-01·Cancer Immunology, Immunotherapy

CAR γδ T cells for cancer immunotherapy. Is the field more yellow than green?

Review

作者: Sakshi, Seth ; Ganapathy, Thamizhselvi ; Radhakrishnan, Rajalingam ; Martin, Sunil

Engineered immune cell therapy to treat malignancies refractory to conventional therapies is modernizing oncology. Although αβ T cells are time-tested chassis for CAR, potential graft versus host disease (GvHD) apart from cytokine toxicity and antigen escape pose limitations to this approach. αβ T cell malignancy challenges isolation and expansion of therapeutic T cells. Moreover, αβ T cells may pose toxicity risk to inflammation sensitive vital tissues bearing the tumor. The HLA independent, multivalent, versatile and systemic anti-tumor immunity increases the desirability of γδ T cells as an alternate chassis for CAR. Indeed, CD19 γδ CAR T cell therapy to treat advanced lymphoma reached a milestone with the fast track status by FDA. However, reduced tumor-toxicity, homing, in vivo persistence and heterogeneity limits the translation of this therapy. The field is gaining momentum in recent years with optimization of gene delivery approaches and mechanistic insights into co-signaling requirements in γδ T cells. There is a renewed interest in customizing design of CAR guided by the biology of the host immune cells. Progress has been made in the current good manufacturing practice compatible expansion and engineering protocols for the δ1 and δ2 T cells. γδ CAR T cells may find its niche in the clinical situations wherein conventional CAR therapy is less suitable due to propensity for cytokine toxicity or off-tumor effect. As the therapy is moving towards clinical trials, this review chronicles the hitherto progress in the therapeutic engineering of γδ T cells for cancer immunotherapy.

2022-01-01·Clinical & Translational Immunology3区 · 医学

Allogeneic CD20‐targeted γδ T cells exhibit innate and adaptive antitumor activities in preclinical B‐cell lymphoma models

3区 · 医学

ArticleOA

作者: Bray, Kevin ; Giner‐Rubio, Ana ; Kennedy‐Wilde, Jackie ; Bai, Lu ; Barca, Taylor ; Tessman, Hayden ; Delfino, Frank ; Papaioannou, Stephanie ; Panuganti, Swapna ; Hayes, Sandra M ; Abbot, Stewart E ; Satpayev, Daulet ; Herrman, Marissa ; Hoopes, Matthew ; Brodey, Mary M ; Azameera, Aruna ; Aftab, Blake T ; Sharma, Kriti ; Sengupta, Ranjita ; Shao, Hui ; Makkouk, Amani ; Hoang, Ngoc T ; Ramanathan, Vidhya Dhevi ; Nishimoto, Kevin P ; Doan, Amy ; Masri, Cynthia ; An, Zili ; Romero, Jason M

AbstractObjectivesAutologous chimeric antigen receptor (CAR) αβ T‐cell therapies have demonstrated remarkable antitumor efficacy in patients with haematological malignancies; however, not all eligible cancer patients receive clinical benefit. Emerging strategies to improve patient access and clinical responses include using premanufactured products from healthy donors and alternative cytotoxic effectors possessing intrinsic tumoricidal activity as sources of CAR cell therapies. γδ T cells, which combine innate and adaptive mechanisms to recognise and kill malignant cells, are an attractive candidate platform for allogeneic CAR T‐cell therapy. Here, we evaluated the manufacturability and functionality of allogeneic peripheral blood‐derived CAR+ Vδ1 γδ T cells expressing a second‐generation CAR targeting the B‐cell‐restricted CD20 antigen.MethodsDonor‐derived Vδ1 γδ T cells from peripheral blood were ex vivo‐activated, expanded and engineered to express a novel anti‐CD20 CAR. In vitro and in vivo assays were used to evaluate CAR‐dependent and CAR‐independent antitumor activities of CD20 CAR+ Vδ1 γδ T cells against B‐cell tumors.ResultsAnti‐CD20 CAR+ Vδ1 γδ T cells exhibited innate and adaptive antitumor activities, such as in vitro tumor cell killing and proinflammatory cytokine production, in addition to in vivo tumor growth inhibition of B‐cell lymphoma xenografts in immunodeficient mice. Furthermore, CD20 CAR+ Vδ1 γδ T cells did not induce xenogeneic graft‐versus‐host disease in immunodeficient mice.ConclusionThese preclinical data support the clinical evaluation of ADI‐001, an allogeneic CD20 CAR+ Vδ1 γδ T cell, and a phase 1 study has been initiated in patients with B‐cell malignancies (NCT04735471).

100 项与 CD19 Universal CAR-γδ T Cells(Guangzhou Bio-gene Technology) 相关的药物交易

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