Breast Cancer Immunotherapy with Anti-TIM-3
Abstract
The immune checkpoint blockade therapeutic atezolizumab (anti-PD-L1) is the first approved immunotherapy for breast cancer, with efficacy demonstrated in combination with the chemotherapy Abraxane (nab-paclitaxel) in metastatic triple-negative breast cancer. This demonstrates that immunotherapy can work in breast cancer, provided the correct therapeutic combinations can be identified. Despite this progress, atezolizumab only showed efficacy in a subgroup of patients with PD-L1 positive disease, the response rate to atezolizumab remains low, and progression-free survival was only extended by 1.7 months. There is thus an urgent need to identify new immunotherapeutic combinations that will increase the number of patients that can be treated, as well as the durability of the responses observed. TIM-3 (T-cell immunoglobulin and mucin domain containing-3) is an immune checkpoint molecule currently being evaluated in dose escalation trials in combination with anti-PD-1 antibodies in lung cancer and melanoma. These trials are being conducted in highly immunogenic tumors based upon dual expression of PD-1 and TIM-3 by cytotoxic T cells, the immune population largely responsible for the efficacy of immunotherapy. However, we have found that TIM-3 is not expressed by cytotoxic T cells in poorly immunogenic breast tumors. We also observe that treatment with anti-PD-1/TIM-3 shows no efficacy in animal models of breast cancer. Instead, we have recently described a unique mechanism of action in breast cancer whereby blocking TIM-3 activates a rare population of dendritic cells, the immune subset that is responsible for controlling cytotoxic T cells. TIM-3 blocking antibodies thereby indirectly enhance the anti-tumor immune response in breast cancer. Critically, we have found that dendritic cell activation only occurs when tumor cells are killed in a manner that releases DNA. Therefore, we propose here to identify combinations of cytotoxic therapy that are efficacious with TIM-3 blockade and then determine if these combinations can elicit a response to anti-PD-L1 in resistant tumors. Finally, we will evaluate the efficacy of our therapeutic combinations in preclinical models of triple-negative and metastatic breast cancer. As TIM-3 is constitutively expressed by dendritic cells in all of the patient samples we have examined to date, it suggests that therapeutic combinations we identify in these studies will be applicable to a majority of patients. Furthermore, it is possible that enhanced cytotoxic T cells responses resulting from anti-TIM-3 combinatorial therapies could increase the number of patients that would be amenable to atezolizumab therapy and/or improve the durability of the response. Results from these studies therefore have the potential to alter the landscape of breast cancer immunotherapy.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010012
Entities
People
- Brian Ruffell
Organizations
- H. Lee Moffitt Cancer Center & Research Institute
- United States Army