Chimeric antigen receptor T cell (CAR T) therapy has demonstrated potentially curative therapeutic efficacies in patients with lymphoma and leukemia.1 This success in hematologic malignancies led to the application of CAR T cell therapy in solid tumors.
The recent clinical trials that have evaluated CAR T cells for effectiveness in eliminating solid tumors have been much less successful. This observation that monotherapy CAR T cell treatment is much less effective for solid tumors has driven the industry into consideration of an alternative strategy for CAR T cells – combination therapies.2
A solid tumor is a heterogeneous population of cells, containing transformed cancer cells, supportive stromal cells and tumor-infiltrating immune cells. Cells of the same cancer type and within the same solid tumor can show distinct morphological and phenotypic profiles. Adjacent cells can have differences in gene expression, cell surface antigens, metabolism, proliferation and metastatic potential. Combinatorial approaches may be a promising strategy to drive CAR T cell therapy toward solid tumors by overcoming tumor heterogeneity.3
A combination therapy combines two or more treatment modalities. Current treatment modalities for cancers include, but are not limited to: small molecule chemotherapy, radiotherapy, antibody (biologic) therapy, surgery, adoptive cell therapy (CAR T cells), gene therapy or oncolytic virus therapy. For example, a recent study showed that allogeneic CAR T cell therapy in combination with a monoclonal antibody has clinical activity and is tolerable in patients with relapsed or refectory large B cell or follicular lymphoma.4
There is evidence from the literature that CAR T cell activity can be enhanced by combing oncolytic virus therapy with CAR T cells when the virus expresses cytokines,5 chemokines,6 an anti-PD-L1 antibody,7 or a Bi-Specific T Cell Engager (BiTE).8 Carl June and his colleagues demonstrated that an oncolytic adenovirus expressing interleukin-2 (IL-2) and tumor necrosis factor-α (TNF-α) enhanced the efficacy of mesothelin-redirected CAR T cells and was associated with enhanced T-cell infiltration to the tumor bed and reduced metastases.5
Additionally, Rachel Grosser and colleagues proposed combination immunotherapy with CAR T cells and checkpoint blockade for the treatment of solid tumors. Checkpoint blockade therapy (anti-PD-1 [anti-programmed cell death protein 1], anti-CTLA-4 [anti-cytotoxic T-lymphocyte-associated protein 4]) can produce durable clinical responses by reactivating an exhausted immune response.8 However, response rates remain relatively low, possibly due to a lack of a tumor-reactive immune infiltrate. CAR T cells may provide the necessary tumor-targeting immune infiltrate and a highly specific antitumor immune response. This can be further amplified by the addition of checkpoint blockade agents, which serve to counteract the immune inhibitory environment undermining optimal CAR T cell efficacy.2
The Preclinical Oncology (PCO) group at Covance is solidly positioned to run combination therapies in mice for drug discovery needs. Our lab was the first to add the IVIS imaging instrument for bioluminescent efficacy studies in the preclinical space and we have been running these studies for 18 years. The PCO group also benefits from state-of-the-art focal beam and generalized radiation as well as several specialized surgery techniques. Table 1 characterizes our wealth of experience in combination therapies run in mouse models.