Pharos Vaccine, Inc.

Dendritic cells (DCs) have a critical effect on the outcome of adaptive immune responses against growing tumors. Recent studies on the metabolism on DCs provide new insights on the functioning of these critical controllers of innate and adaptive immunity. DCs within the tumor microenvironment (TME) often exist in an inactive state, which is thought to limit the adaptive immune response elicited by the growing tumor. Tumor-derived factors in the TME are known to suppress DC activation and result in functional alterations in DC phenotype. We are now beginning to appreciate that many of these factors can also induce changes in immune cell metabolism. In this review, we discuss the functional alternation of DC phenotype by tumor metabolites.

Treatment with chimeric antigen receptor (CAR)-modified T cells targeting CD19 has proved successful in patients with relapsed/refractory B cell malignancies. However, long-term follow-up indicates that remission in a substantial proportion of patients is not sustainable. Most patients that experience recurrence have tumors and lost the CAR-T cells. To maintain the activity of CAR-T cells, Raji-B-NDG mice were treated sequentially with CAR-T-19 cells and homologous cells expressing human CD19 to promote expansion of CAR-T cells. Sequential treatment of mice with CAR-T-19 cells followed by Raji tumor cells led to marked prolongation of survival. The best case scenario after sequential treatment was a survival time of more than 200 days; the average survival time of mice in the non-sequential treatment group was 80 days. We treated mice with autologous CD19-modified T cells after initial treatment with CAR-T-19 cells. The overall survival and recurrence-free survival times of mice receiving sequential treatment were significantly longer. The percentages of CAR⁺ T cells in peripheral blood increased. Sequential therapy with autologous CAR-T-19 and aT19 cells provides a new strategy for generating memory CAR-T cells, which may lead ultimately to increased clinical efficacy.

The aim of this study was to determine the potential for an additive effect from combining treatments with tolerogenic dendritic cells (tDCs) and etanercept (ETN) in a case of established type II collagen-induced arthritis (CIA).CIA mice were treated with type II collagen-pulsed tDCs either alone or in combination with ETN.We compared the effects of monotherapy with tDCs or ETN with the effect of combination treatment on the resultant rheumatoid arthritis using histopathol. analyzes and measurements of paw volumes, regulatory T cell populations, and cytokine levels.The clin. and histol. anal. revealed an additive effect from the combination therapy.Monotherapy with tDCs showed a tendency to ameliorate arthritis symptoms, while monotherapy with ETN reduced the paw swelling at 3 days after administration, but was not effective toward the end of the exptl. period.The combined treatment group also showed a marked inducement of the regulatory T cells and Th2 cytokines that are affected by tDCs compared with those of either untreated or ETN-treated CIA mice.ETN administered in combination with tDCs provided a substantially higher level of clin. benefit at the cellular level to CIA mice than the administration of either of these agents alone.