Combining Lymph Node Targeting Cancer Vaccines with Systemic Immunotherapy to Recruit an Innate and Adaptive Attack Against Established Tumors
Darrell J. Irvine
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
Solid tumors evade destruction by the immune system through many parallel pathways of immunosuppression, and combination therapies may be required to overcome this network of immune blockade.We hypothesize that therapeutic vaccines have an important role to play in successful combination immunotherapies, but existing vaccine strategies may lack the potency needed for treating advanced cancer.We thus have explored factors limiting the potency and efficacy of one clinically important vaccine modality, peptide vaccines.We find that peptide vaccines are limited by both rapid degradation in vivo and poor lymphatic trafficking, leading to low levels of antigen that do not persist in lymph nodes.Using multiple strategies to address these issues including introduction of albumin-binding moieties or fusion to albumin domains that promote lymphatic trafficking and block peptide degradation, we find that peptide vaccine responses can be increased by as much as 50-fold in mice. Using both established and engineered immunotherapy reagents, we discovered a combination immunotherapy employing these lymph node targeting vaccines that recruits a diverse set of innate and adaptive immune effectors, enabling robust elimination of tumor burdens that to our knowledge have not previously been curable by treatments relying on endogenous immunity. Maximal anti-tumor efficacy required four components: a tumor antigen targeting antibody, an extended-pharmacokinetics IL-2 molecule, anti-PD-1, and the vaccine. This combination elicited cures of large established tumors in multiple transplanted tumor models, and induced sustained tumor regression in an autochthonous BRrafV600E/Pten-/- melanoma model. Multiple innate immune cell subsets, CD8+ T-cells, and cross-presenting DCs were critical to successful therapy. Treatment enhanced antibody-mediated tumor antigen uptake, and promoted antigen spreading. These results demonstrate the capacity of the endogenous immune response to destroy large, established tumors and suggests essential characteristics of an integrated immune response capable of overcoming immunosuppressive tumors.
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