PR/8/34/H1N1; PR8) and boost (HA expressing recombinant modified Vaccinia Ankara; rMVA-HA) vaccinations either before (neoadjuvant) or after (adjuvant) ...
Combining Prime-Boost Anti-tumour Vaccination with Debulking Surgery for the Treatment of Solid Tumours. Scott A Fisher, Amanda L Cleaver, Andrea Khong, Theresa Connor, Ben Wylie, Daphne Lakhiani, Catherine Boylen Bruce W Robinson and Richard Lake.
National Centre for Asbestos Related Diseases, School of Medicine and Pharmacology University of Western Australia. Perth, Australia. 6009.
Key words: Cancer, Immunotherapy, Regulatory T cells, anti‐tumour vaccines, Surgery. The development of effective anti‐cancer immunotherapies is of critical importance. While many anti‐cancer immunotherapies have had limited success as monotherapies, their efficacy may be enhanced when combined with conventional therapies such as surgery or chemotherapy. Here we describe the development of a prime‐boost (P/B) anti‐tumour vaccination protocol that significantly improved survival outcome when combined with partial debulking surgery and targeted suppression of regulatory T cells (Treg). Using our well established AB1‐HA mouse tumour model, tumour bearing mice received prime (influenza A PR/8/34/H1N1; PR8) and boost (HA expressing recombinant modified Vaccinia Ankara; rMVA-HA) vaccinations either before (neoadjuvant) or after (adjuvant) 75% debulking surgery. Only neoadjuvant P/B vaccination induced tumour‐specific immunity that resulted in significantly delayed tumour growth when combined with debulking surgery; although this was not sufficient to prevent tumour outgrowth. Depletion studies demonstrated that CD8 T cells were essential for the delay in tumour growth. Interestingly, depletion of CD4 T cells and more specifically Treg during neoadjuvant P/B vaccination lead to cures in greater than 60% of treated mice. These surviving mice also resisted tumour rechallenged indicating the establishment of long term anti‐tumour immunological memory. Taken together, these data suggest that vaccine induced anti‐tumuor immunity is “restrained” by Treg and can be enhanced by the targeted removal of Treg. Based on these findings we are actively investigating whether combining novel immunotherapies with conventional treatments in the absence of “immunological restrainers” such as Treg and myeloid derived suppressor cells (MDSC) may generate effective therapy for MM and other solid cancers. Support: This research was funded by a research grant from the Workers’ Compensation Dust Diseases Board, an agency of the New South Wales Government.
