In situ vaccination: Cancer immunotherapy both personalized and off-the-shelf

Abstract

As cancer immunotherapy continues to benefit from novel approaches which cut immune 'brake pedals' (e.g. anti-PD1 and anti-CTLA4 antibodies) and push immune cell gas pedals (e.g. IL2, and IFNα) there will be increasing need to develop immune 'steering wheels' such as vaccines to guide the immune system specifically toward tumor associated antigens. Two primary hurdles in cancer vaccines have been: identification of universal antigens to be used in 'off-the-shelf' vaccines for common cancers, and 2) logistical hurdles of ex vivo production of individualized whole tumor cell vaccines. Here we summarize approaches using 'in situ vaccination' in which intratumoral administration of off-the-shelf immunomodulators have been developed to specifically induce (or amplify) T cell responses to each patient's individual tumor. Clinical studies have confirmed the induction of systemic immune and clinical responses to such approaches and preclinical models have suggested ways to further potentiate the translation of in situ vaccine trials for our patients.

Keywords: Cancer immunotherapy; Checkpoint blockade; Dendritic cells; In situ vaccination; Oncolytic viruses; Toll like receptors.

Figure 1

Effective in situ vaccination uses local or intratumoral immunomodulation to produce abundant, highly activated, antigen presenting cells such as dendritic cells (DC) able to present the full repertoire of tumor‐associated antigens (TAA) to tumor‐reactive T cells which, in turn, mount a systemic anti‐tumor immune response. Optimally, this approach occurs through: 1) increasing intratumoral DC populations, by recruitment or local proliferation (e.g. with intratumoral Flt3L administration); 2) inducing immunogenic tumor cell death locally or systemically to release TAA (e.g. with radiotherapy, chemotherapy, or oncolytic virus); 3) enhancing TAA uptake, processing and presentation or cross‐presentation by DC (e.g. with heat shock proteins or using prime‐boost oncolytic viral strategies); 4) promoting antigen‐loaded DC to trafficking to secondary lymphoid tissue 5) presentation or cross‐presentation to antigen‐specific T cells; 6) trafficking of T cells to tumor sites systemically; 7) inhibition of multiple levels of immunosuppression, including cells and molecules suppressing T cells both at the vaccine site as well as distant tumor sites (e.g. with intratumoral or systemic checkpoint blockade).