Oral Presentation Eradicate Cancer 2018

Tumours typically express many mutations, As these mutations are ‘neo’ to the body, i.e. would not have undergone self tolerance, it is logical to postulate that they might be able to induce specific cytotoxic T lymphocytes (CTLs), especially in the context of immune checkpoint blockade immunotherapy (ICPB). Positive outcomes to ICPB are associated with high neo-antigen loads and with neo-antigen specific CTL responses.   However only around 20% of patients respond to ICPB.

In order to examine ways in which the non-responders might become responders we examined several strategies to improve response rates, using anti-CTLA4 initially as the ICPB therapy in BALB/c mice in which Uqcrc2 has been defined as a DNA/RNAseq-identified neo-antigen in AB1 tumor lines induced by a relevant human carcinogen(1).

1. a) We first examined therapy-induced changes in T-cell responses against Uqcrc2. Anti-CTLA4 alone increased the magnitude of responses against Uqcrc2. Anti-CTLA4 combined with anti-GITR induced determinant spreading, unmasked responses against a new neo-antigen UNC45A that was undetectable during normal tumour growth. Immunogenic chemotherapy also unmasked responses against UNC45A, suggesting that subdominant neo-antigens can be unmasked by the appropriate immunotherapy.
2. b) We then evaluated neo-antigen vaccination strategies. Uqcrc2 vaccination best protected against tumor growth when administered in combination with partial Treg depletion (Foxp3.DTR mice), suggesting that neo-antigen vaccination will only be maximally effective when administered in combination with therapies that modulate existing immune restraints, including Tregs.
3. c) We determined optimal anatomical location for tracking neo-antigen CTL responses and identified the draining lymph node as an optimal, though not exclusive, location for response testing compared to blood or tumor.

            We are currently studying the immunogenicity of non-SNVs and the relationship between NGS and proteomic analysis of neo-antigens. We will commence a neo-antigen vaccine trial in early 2018.  Overall, these observations have important translational implications for identification of key neo-antigens, choice of therapy and monitoring of anti-tumor responses.