Overcoming Tumour Resistance to Adoptive Immunotherapy by Enhancing CTL function

Abstract

© 2019 Tinaz Monshizadeh SamieiWhile adoptive cell transfer (ACT) therapy using chimeric antigen receptor (CAR) T cells can be effective in the treatment of haematological B cell malignancies, the treatment of solid tumours has been challenging. Limiting factors such as low levels of CAR T cell activity and poor infiltration into solid tumours, antigen heterogeneity and immunosuppressive microenvironments are playing important roles in solid tumour resistance to CAR T cell therapy. Therefore, a better understanding of these limiting factors is necessary for overcoming these challenges and addressing tumour resistance to immunotherapy. Multiple studies have investigated different strategies to increase the efficacy of CAR T cell therapy in solid tumours including the modification of CAR T cell structure and using a combination of checkpoint inhibitors. Recently a study from our laboratory demonstrated the eradication of established large tumours including E0771-Her2 breast cancer, 24JK-Her2 sarcoma, and MC38-Her2 colon carcinoma using adoptive cell transfer incorporating vaccination (ACTIV) therapy. In ACTIV therapy, tumour-bearing mice were preconditioned with whole-body irradiation and then treated with dual specific CAR T cells and vaccinia virus VV-gp100 in addition to IL-2 administration. The dual specific CAR T cell possessed a CAR specific for Her2 together with a TCR specific for the premelanosome protein, Pmel. Pmel serves as a strong immunogen that is incorporated in a vaccinia virus, VV-gp100, in ACTIV therapy and facilitates dual-specific (CARaMEL) T cell activation, proliferation and infiltration. Despite the significant results of ACTIV therapy in the elimination of the above tumours, we identified a relatively resistant tumour, AT3-Her2 breast cancer tumour. Since an understanding of mechanisms of tumour resistance is essential for potential extension of ACTIV therapy to a broader range of tumours, we used E0771-Her2 and AT3-Her2 tumours as comparative tumour models for studying limitations in effective ACTIV therapy and proposing potential approaches to overcome those limitations. In our study E0771-Her2 and AT3-Her2 tumours were representative of sensitivity and resistance to ACTIV therapy respectively. We identified the relative resistance of AT3-Her2 tumours to CARaMEL T cell cytotoxicity and poor T cell infiltration into tumours as two main limiting factors in effective ACTIV therapy of AT3-Her2 tumours. We used two approaches to address these challenges. Firstly, we used the combination of oncolytic vaccinia virus VV-dd with ACTIV therapy and showed a significant improvement in therapeutic efficacy of ACTIV therapy. In addition, we showed that oncolytic VV-dd can increase apoptosis in AT3-Her2 tumours. Analysis of T cell proliferation and distribution showed a higher T cell infiltration using ACTIV+VV-dd therapy. In another approach to address the relative resistance of AT3-Her2 tumours to CARaMEL T cell killing, we used an IAP antagonist, SMAC-mimetic drug, named AZD5582 in combination with ACTIV therapy. Our results showed a significantly higher level of CARaMEL T cell cytotoxicity using a combination of the CARaMEL T cells with AZD5582 in vitro. In addition, inhibition of AT3-Her2 tumour growth increased remarkably using AZD5582 in combination with ACTIV therapy. Further analysis showed that this therapy could also increase T cell infiltration into AT3-Her2 tumours and induce apoptosis in tumour cells. Therefore, both strategies demonstrated the promising potential for increasing the therapeutic efficacy of ACTIV therapy and its extension to a broader range of solid tumours

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11343/233795oai:jupiter.its.unimelb.edu.au:11343/233795
Last time updated on January 27, 2020

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