Overcoming Tumour Resistance to Adoptive Immunotherapy by Enhancing CTL function
AuthorMonshizadeh Samiei, Tinaz
AffiliationSir Peter MacCallum Department of Oncology
Document TypePhD thesis
Access StatusThis item is embargoed and will be available on 2022-01-13.
© 2019 Tinaz Monshizadeh Samiei
While 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.
KeywordsImmunotherapy, CAR T cell, Vaccinia virus
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