Immunotherapy and targeted hyperthermia
Immune checkpoint therapy has become the first widely adopted and successful immunotherapy for the treatment of late stage melanoma and holds great promise for achieving success in a broad range of cancers. Up to ~40% of patients experience complete responses, showing long term remission. The key challenges of immune checkpoint therapy are expanding the population of complete responders and limiting toxicity. While the reasons for low response rates are not completely understood, the current belief is that tumors produce numerous immunosuppressive factors creating a “nonimmunogenic” tumor microenvironment. The path forward is believed to be combinatorial approaches that convert a nonimmunogenic (“cold”) tumor to an immunogenic (“hot”) one that will respond to ICP therapy. However, current combinatorial approaches (e.g. chemotherapy, radiation, targeted therapy) exhibit significant toxicity (chemo and targeted therapy) and/or resistance (chemo and radiation). In addition, there currently exists a lack of knowledge as to which combinatorial approach best matches an individual during a treatment course due to the lack of understanding of the interplay of combinatorial approaches and immune checkpoint therapy. Therefore, a continued unmet need exists for combinatorial therapies that can enhance immunotherapies with limited toxicity profiles and an understanding of the synergy between combinatorial approaches.
We are developing targeted hyperthermia as a combinatorial approach to immunotherapy. Targeted hyperthermia (Figure) utilizes a utilizes a targeted nanoparticle to specifically localize at the cancer site that heats up when irradiated with a laser (i.e. photothermal therapy). Local hyperthermia induces immunogenic cell death within the tumor, converting a cold tumor to an immunogenic, hot one, stimulating adaptive immune responses that activate cytotoxic T cells against the cancer. This effect synergizes with immunotherapy and has shown to increase response rates in animal models.
Figure. Targeted hyperthermia increases response rates to immunotherapy. 1) Systemic administration of nanoparticles localize to the tumor and 2) irradiation with an external laser are the main components of targeted hyperthermia. 3) Tumor hyperthermia initiates the apoptosis responses that upregulate tumor specific antigens (TSA) and expression of heat shock proteins (HSP) and damage associated molecular patterns (DAMPs). Necrosis releases TSA and HSP-TSA complexes that activate antigen presenting dendritic cells (DC). HSP receptors (HSPR) on DCs recognize HSP-TSA complexes, activating natural killer (NK) effector cells and release of cytokines and chemokines. 4) DCs traffic TSA to the lymph nodes (LN) where they activate T cells with T cell receptors (TCR) specific to the TSA. Activated T cells upregulate inhibitory surface receptors (PD-1 and CTLA-4), and 5) traffic back to the primary and distant/metastatic tumors throughout the body, initiating TCR mediated killing of tumor cells. In the absence of ICP therapy, inhibitory ligands on the tumor cells (e.g. PD-L1) would down-regulate and inhibit a full response; however, blocking the immune checkpoints allows for a full, uninhibited immune response, ultimately resulting in tumor cell killing and immune memory.
References
A.J. Moy, J.W. Tunnell, Combinatorial immunotherapy and nanoparticle mediated hyperthermia, Adv. Drug Deliv. Rev. (2017), http://dx.doi.org/10.1016/j.addr.2017.06.008
