γδ-Enriched CAR-T cell therapy for bone metastatic castrate-resistant prostate cancer

Abstract

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.

Advancements in γδT cell engineering: paving the way for enhanced cancer immunotherapy

“…Given the wealth of limitations associated with αβT cells, γδT cells are garnering interest as an alternative for CAR-T therapy. These cells do not instigate GvHD, curb antigen escape resulting in decreased relapse rates, and retain beneficial traits such as a less differentiated phenotype with enhanced antigen presentation capacity ( 125 , 151 ). With these advantages, γδ CAR-T cells may have the potential to overcome the obstacles that have historically troubled conventional αβ CAR-T therapy.…”

“…Owing to the deficit of tumor-specific antigens, lineage-specific antigens have been a key focus in CAR T cell development. Under investigation are promising candidates like CD19 ( 153 , 154 ), GD2 ( 130 , 155 ), GPC-3 ( 128 ), CD123 ( 131 , 156 ), CD5, CEA, CD20 ( 10 ), B7H3 B7H3 ( 157 ), and PSCA ( 151 ) ( Table 2 ). While CD19-targeting CAR-T products have earned FDA approval for treating B-cell lymphoma and leukemia, they carry risks, like CRS, neurotoxicity, and B-cell aplasia, primarily due to on-target off-tumor toxicities ( 152 , 153 ).…”

“…In a murine model of bone metastatic prostate cancer, γδ CAR-T cells persisted in the tumor-bearing tibia for approximately 21 days post-infusion. However, these cells exhibited an upregulation of PD-1 expression while simultaneously losing expression of activation markers ( 151 ). Consequently, the combination of therapies such as ICT01 and pembrolizumab, an anti-PD1 antibody, exhibited favorable safety profiles in a phase I clinical trial (NCT04243499).…”

“…Consequently, the combination of therapies such as ICT01 and pembrolizumab, an anti-PD1 antibody, exhibited favorable safety profiles in a phase I clinical trial (NCT04243499). This suggests that the co-administration of CAR-T/bsTCE therapy with anti-PD-1/PD-L1 antibodies could potentially boost treatment benefits ( 151 ).…”

Harnessing γδ T Cells against Human Gynecologic Cancers

“…For instance, treating 132 patients with tumors of multiple histological origins with multiple infusions of allogeneic Vγ9Vδ2 T cells, Xu and colleagues identified 8 liver cancer patients and 10 lung cancer patients who showed prolonged survival [ 75 ]. Since Vγ9Vδ2 T cells circulate and are dominant in blood, they could be ideal for treating hematological tumors or bone marrow metastases [ 76 ]. However, as aforementioned, the γδ T-cell populations that spontaneously home to human gynecologic malignancies (e.g., ovarian cancer [ 3 ]) are Vδ1 and, to a lesser extent, Vδ3 lymphocytes.…”