Road testing new CAR design strategies in multiple myeloma

Abstract

A deeper understanding of basic immunology principles and advances in bioengineering have accelerated the mass production of genetically-reprogrammed T-cells as living drugs to treat human diseases. Autologous and allogeneic cytotoxic T-cells have been weaponized to brandish MHC-independent chimeric antigen receptors (CAR) that specifically engage antigenic regions on tumor cells. Two distinct CAR-based therapeutics designed to target BCMA are now FDA-approved based upon robust, sustained responses in heavily-pretreated multiple myeloma (MM) patients enrolled on the KarMMa and CARTITUDE-1 studies. While promising, CAR T-cells present unique challenges such as antigen escape and T-cell exhaustion. Here, we review novel strategies to design CARs that overcome current limitations. Co-stimulatory signaling regions were added to second-generation CARs to promote IL-2 synthesis, activate T-cells and preclude apoptosis. Third-generation CARs are composed of multiple co-stimulatory signaling units, e.g., CD28, OX40, 4-1BB, to reduce exhaustion. Typically, CAR T-cells incorporate a potent constitutive promoter that maximizes long-term CAR expression but extended CAR activation may also promote T-cell exhaustion. Hypoxia-inducible elements can be incorporated to conditionally drive CAR expression and selectively target MM cells within bone marrow. CAR T-cell survival and activity is further realized by blocking intrinsic regulators of T-cell inactivation. T-Cells Redirected for Universal Cytokine Killing (TRUCKs) bind a specific tumor antigen and produce cytokines to recruit endogenous immune cells. Suicide genes have been engineered into CAR T-cells given the potential for long-term on-target, off-tumor effects. Universal allo-CAR T-cells represent an off-the-shelf source, while logic-gated CAR T-cells are designed to recognize tumor-specific features coupled with Boolean-generated binary gates that then dictate cell-fate decisions. Future generations of CARs should further revitalize immune responses, enhance tumor specificity and reimagine strategies to treat myeloma and other cancers.

Combination of CAR‑T cell therapy and radiotherapy: Opportunities and challenges in solid tumors (Review)

“…The NKG2D system serves an indispensable role in cancer immune surveillance, and NKG2D-ligand is delivered on the surface of glioblastoma cells and radiotherapy is known to induce its expression (31,94). After systemic administration, chNKG2D CAR-T cells moved to the brain tumor site through the blood brain barrier, and no adverse events were reported (95). The results indicated that local tumor irradiation promoted the movement of CAR-T lymphocytes to the tumor site and increased the expression of IFN-γ in a NKG2D-based chimeric antigen receptor construct (chNKG2D) in CAR-T cells.…”

Shutting off the fuel supply to target metabolic vulnerabilities in multiple myeloma

“…Altered cellular metabolism also reduces the anti-myeloma effect of standard-of-care agents, e.g., PIs and immunomodulatory drugs (IMiDs). Metabolic changes within the TME further decreases the beneficial anti-myeloma effects of PIs and IMiDs, monoclonal antibodies and cellular immunotherapies ( 14 , 15 , 23 , 36 ). Despite the development of novel anti-myeloma drugs over the past two decades, disease heterogeneity, high-risk disease, early relapse and treatment resistance remain challenges ( 14 , 20 , 22 , 24 , 33 ).…”

“…Metabolic changes within the TME further decreases the beneficial anti-myeloma effects of PIs and IMiDs, monoclonal antibodies and cellular immunotherapies ( 14 , 15 , 23 , 36 ). Despite the development of novel anti-myeloma drugs over the past two decades, disease heterogeneity, high-risk disease, early relapse and treatment resistance remain challenges ( 14 , 20 , 22 , 24 , 33 ). Moreover, subclonal heterogeneity of PCs evolves alongside disease progression through the selection of genetically and metabolically adapted subclones ( 37 , 38 ).…”

Vactosertib, a novel TGF-β type I receptor kinase inhibitor, improves T-cell fitness: a single-arm, phase 1b trial in relapsed/refractory multiple myeloma

“…Recent studies have harnessed the power of T-cells engineered to express chimeric antigen receptors (CARs) to treat MM and other hematologic malignancies (56)(57)(58)(59). Barriers following 24 h co-culture.…”