If a problem is too big for one troop, it’s time to call for backup. While systemic injections of CAR T cells have been notably successful in the treatment of hematological malignancies, their success in solid tumors has been limited due to a number of factors, including identifying suitable targets, inefficient trafficking of CAR T cells to the tumor site, an immunosuppressive microenvironment in the tumor bed, and diversity in the expression of tumor antigens that allows some malignant cells to escape the immune attack. Smith et al. have cleverly tackled some of these challenges by developing an implantable biopolymer that delivers CAR T cells and STING agonist directly to the surfaces of solid tumors.
The biomaterial used in this study consists of a porous scaffold made from a naturally occurring polysaccharide that has already been approved by the FDA for human use. Microparticles containing STING agonist were incorporated during scaffold fabrication and CAR T cells were infused into the scaffold disc just before use.
The oncogene-driven KPC mouse model of pancreatic cancer was used to test the biopolymer delivery system. When the biopolymer was loaded only with NKG2D CAR T cells targeting the native antigen RAE1 on the tumor cell surface, tumor growth was reduced, but ultimately cancer progressed due to the presence of immune escape variants. To address this issue, the researchers added STING agonists to convert the tumor bed to an endogenous vaccine that launches the host’s cancer immunity cycle, creating not only an additive, but a synergistic effect.
The dually-loaded biomaterial implant completely cleared tumors in four out of ten mice, while the remaining six mice showed substantial regression. Upon a rechallenge with KPC tumor cells, long-term surviving mice were fully protected and showed no signs of new tumor growth, demonstrating lasting, systemic antitumor immunity. Compared to a control group that received the same active agents via direct in situ vaccination, use of the biopolymer device improved survival dramatically, and the slow release of adjuvant from the biomaterial bypassed the need for the repeated injections normally required to stimulate host immunity.
To prove effectiveness on other solid cancer types, the device was tested on sites of incompletely resected melanomas in mice with similar results - six of ten mice completely cured and protected upon tumor rechallenge, while the remaining four showed substantially delayed relapse.
Importantly, this tumor control occurred despite dramatic cell to cell heterogeneity in the expression of the CAR target on the surface of tumor cells, suggesting a broadening of the immune response. To prove this hypothesis, the researchers genetically marked the donor CAR T cells before infusion, and used tumor cells containing a unique viral neoantigen. When the T cell response was measured, host T cells specific to the viral neoantigen could be detected, elegantly demonstrating the launch of an endogenous antitumor immune response.
KPC mice treated with biomaterials co-delivering CAR T cells and STING agonists did not show any significant side effects nor did they require lymphodepletion, a common and potentially fatal pretreatment regimen used with CAR therapy.
Future challenges for the use of biopolymer delivery devices include taking on larger tumors and optimizing the selection of antitumor T cell therapy, host-immune-stimulating agents, and other agents that might improve the immune response to tumor cells.
by Lauren Hitchings