Targeting HSP70 to Immune Effector Cells to Overcome the Immune Suppressive Myeloma Microenvironment
Robert Orlowski
PhD, MDThe University of Texas MD Anderson Cancer Center
Project Term: July 1, 2023 - June 30, 2026
Development of a strong anti-cancer immune response requires coordinated action of the innate and adaptive parts of the immune system, but cancer cells alter their environment to suppress virtually every step in this process, which promotes cancer progression and treatment resistance. One promising strategy could be to target Heat shock protein 70 (HSP70), which plays an important role in both innate and adaptive immunity, and we therefore developed a series of novel antibodies to HSP70, one of which cured mice of multiple myeloma. Based on strong preliminary data, we propose additional studies to better understand how this antibody activates various types of immune cells, how it works against both cancer cells and modifies the immune environment in mouse models, and how it could work even better in combination with other agents against myeloma. Since this antibody is already being developed into a drug for phase I clinical trials, these studies will directly inform its use in the clinic against multiple myeloma, and possibly against other blood-related cancers such as B-cell lymphomas.
Development of a strong anti-cancer immune response requires coordinated action of the innate and adaptive parts of the immune system. Cells of the innate arm, including natural killer (NK) cells and macrophages, directly kill cancer cells and release tumor-derived antigens, which are picked up by dendritic cells (DCs). These DCs then present antigens to T-cells and B-cells, which are part of the adaptive immune arm, and the T-cells become activated and travel to tumors, where they attack and kill cancer cells. Frustratingly, cancer cells alter their neighborhood, also called the tumor microenvironment (TME), to suppress virtually every part of these immune responses, and this enables cancer progression and treatment resistance. Therefore, new ways to reverse this immune suppression would be welcome additions to our options for therapy of myeloma, and could also be used against other blood-related cancers, and possibly solid tumors as well.
One promising strategy could be to target Heat shock protein 70 (HSP70), which plays an important role in both innate and adaptive immunity. HSP70 released from cancer cells and bound to tumor-derived antigens delivers these important triggers of the immune response to DCs and T-cells, which helps develop T-cell-mediated immunity. Also, HSP70 uptake can activate other immune cells even in the absence of antigen, including T-cells, macrophages, and NK cells. With this reasoning, we developed a series of novel antibodies to HSP70, tested them for activity in a mouse myeloma model, and selected clone 77A for study because, excitingly, it cured some of these mice. Studies of the mechanism by which 77A works showed it binds HSP70 associated with antigens more strongly than HSP70 alone, and forms complexes that are taken up into cells much better than is HSP70 by itself. This induced DC maturation and antigen presentation, NK cell activation, and a T-cell cytotoxic phenotype that indicates they are better cancer killers. Finally, 77A showed activity in two other mouse myelomas, including the immune-competent Vk*MYC model that predicts well for the efficacy of agents in human patients.
Our initial data support the important possibility that increasing HSP70 and HSP70-tumor antigen complex uptake into immune cells may reverse the suppressive TME and strengthen immune responses. To prove this, we propose the following Aims:
1. To study the interactions of 77A and 77A/HSP70 complexes with immune cells and the impact of their uptake
2. To validate the activity of 77A in models that reflect the biology of myeloma in people, and examine the effects on the TME
3. To evaluate the possibility that 77A could work even better in combination with other agents that target the immune TME
Since 77A is currently being converted into a drug in preparation for phase I trials, these studies will directly support its translation to the clinic for multiple myeloma, and possibly other blood-related cancers as well.