Combination therapies in oncology: The future of CAR T cell therapy for solid tumors? 

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.  

Contact the preclinical oncology scientific team to learn more. 

Table 1. Covance Preclinical Oncology by the Numbers:

Numbers provided are good faith estimates.
*A combination study is defined as those studies that are run with two or more treatment modalities (radiation therapy, gene therapy, cell therapy, small molecule drugs, biologic drugs, CAR T or CAR NK cells, any adoptive cell therapy, oncolytic virus).
ABSL2: Animal Biosafety Level 2; BLI: Bioluminescent Imaging; CAR NK: Chimeric antigen receptor natural killer cell; CAR T: Chimeric Antigen Receptor T cell; IVIS: in vivo imaging system. 

Key Links for More Information:

Bioluminescence Imaging

CAR T Cell Persistence

Tumor Models

Imaging Expertise

Preclinical Oncology Posters

Radiation and Anti-CTLA-4 Therapy

Oncology Models and Technology Spotlights  

Measuring Human Cytokines in Mouse Matrix by MSD

References

1.      Boyiadzis MM, Dhodapkar MV, Brentjens RJ, Kochenderfer JN, Neelapu SS, Maus MV, et al. Chimeric antigen receptor (CAR) T therapies for the treatment of hematologic malignancies: clinical perspective and significance. J Immunother Cancer. 2018;6(1):137.

2.      Grosser R, Cherkassky L, Chintala N, Adusumilli PS. Combination immunotherapy with CAR T cells and checkpoint blockade for the treatment of solid tumors. Cancer Cell. 2019;36(5):471–82.

3.      Watanabe K, Kuramitsu S, Posey AD Jr, June CH. Expanding the therapeutic window for CAR T cell therapy in solid tumors: the knowns and unknowns of CAR T cell biology. Front Immunol. 2018;9:2486.

4.      Targeted Oncology. Novel CAR-T cell therapy combination shows preliminary activity in R/R B-cell lymphoma. Available from: https://www.targetedonc.com/view/novel-car-t-cell-therapy-combination-shows-preliminary-activity-in-r-r-b-cell-lymphoma. Accessed June 2021.

5.      Watanabe K, Luo Y, Da T, Guedan S, Ruella M, Scholler J, et al. Pancreatic cancer therapy with combined mesothelin-redirected chimeric antigen receptor T cells and cytokine-armed oncolytic adenoviruses. JCI Insight. 2018;3:99573.

6.      Nishio N, Diaconu I, Liu H, Cerullo V, Caruana I, Hoyos V, et al. Armed oncolytic virus enhances immune functions of chimeric antigen receptor-modified T cells in solid tumors.Cancer Res. 2014;74:5195–205. 

7.      Rosewell Shaw A, Porter CE, Watanabe N, Tanoue K, Sikora A, Gottschalk S, et al. Adenovirotherapy delivering cytokine and checkpoint inhibitor augments CAR T cells against metastatic head and neck cancer. Mol Ther. 2017;25:2440–51.

8.      Wing A, Fajardo CA, Posey AD Jr, Shaw C, Da T, Young RM, et al. Improving CART-cell therapy of solid tumors with oncolytic virus-driven production of a bispecific T-cell engager. Cancer Immunol Res. 2018;6:605–16.