Combined prophylactic and therapeutic vaccination in a preclinical model of MMR-D-related cancer

• Applicant: Privatdozentin Claudia Maletzki, Ph.D.
• Subject Area: General and Visceral Surgery ; Hematology, Oncology
• Term: from 2014 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 266360457

Mismatch Repair Deficiency (MMR-D)-related tumors either arise sporadically or in the context of hereditary disorders. Two clinically relevant tumor syndromes with MMR-D include Lynch Syndrome and constitutional MMR-D. In both cases, life-time risk of cancer is high. Due to the high abundance of frameshifted neo-epitopes on the tumor cells’ surface, which results from an ultramutated tumor phenotype, MMR-D defines a molecular subtype with great potential to be targeted immunologically. In a proof-of-concept study using whole tumor lysates we were able to induce delayed tumorigenesis and prolonged survival in a clinically-relevant mouse model for MMR-D-related diseases (= MLH1 knock out mice). Of note, gastrointestinal tumorigenesis was substantially delayed, while lymphomagenesis was only marginally affected. In both cases, tumor resection specimens from vaccinated mice revealed increased mutations in coding regions of MMR-D related target genes as well as upregulation of immune-checkpoint molecules, most likely representing an acquired resistance mechanism. To refine this approach and to counteract vaccination-induced immune escape, immune-checkpoint blocking antibodies (anti-PD-L1, anti-LAG-3) will be given as second-line therapy after vaccination with the aim to induce complete tumor regression. The prophylactic approach focusses on immune-modulatory pharmacological intervention, based on our previous finding of a slight immunosuppression present in MLH1-/- mice early in tumorigenesis quite likely promoting tumor progression. As immune-modulatory agent, the cycline-dependent kinase inhibitor Abemaciclib will be given prophylactically. This substance has only recently been shown to polarize immune responses and to enhance tumor immunogenicity. In vivo proof of efficacy is, however, still pending. Hence, in conjunction with the immune-stimulating tumor lysate we here aim to prevent tumorigenesis of both gastrointestinal and lymphoid origin more efficiently. Finally, the immunogenic potential of our identified MMR-D-associated antigens will be tested in an in vivo proof of concept experiment. Mice will be vaccinated prophylactically with two different peptide mixes. To examine immune-mediated effects, in vivo monitoring of tumor growth (PET/CT imaging) as well as detailed functional and immunological methods will be applied (flow cytometric phenotyping/Th1-Th2 cytokine profiles, ELISpot, gene expression assays, mutational analysis).Results obtained from these studies will help moving a step closer to combat MMR-D-related cancer – in a therapeutic and – of particular relevance – even prophylactic setting.

• DFG Programme: Research Grants