At NewYork-Presbyterian/
“For years we have been trying to break the ceiling of immunotherapy response to TNBC, a highly aggressive breast cancer that tends to be seen in young women and in African American women,” says Dr. Demaria, principal investigator of the preclinical study who conducted the research within the Department of Radiation Oncology at NewYork-Presbyterian/
For years we have been trying to break the ceiling of immunotherapy response to TNBC, a highly aggressive breast cancer that tends to be seen in young women and in African American women. The goal of this study was to address the challenges of resistance to immunotherapy in TNBC and improve outcomes in a broader patient population.
— Dr. Sandra Demaria
Understanding the TME in TNBC tumors
Seeking to amplify the immune response, Dr. Demaria and the study team explored the intricate TME in TNBC tumors. The TME is a network of fibroblasts and immune cells including T lymphocytes (T-cells), B lymphocytes (B cells), and macrophages that play a critical role in a tumor’s response to immunotherapy. Within the TME, the myeloid compartment includes granulocytes, monocytes, macrophages, and dendritic cells. Dendritic cells present tumor-derived antigens to T-cells to activate the immune response.
Radiation therapy promotes the release of tumor antigens and their uptake by dendtitic cells. CTLA-4 inhibitors, a type of immune checkpoint inhibitors, work by improving T-cell activation by dendritic cells and preventing T cell silencing by immunosuppressive cells present in the TME. T cells are powerful killers of virally-infected cells and cancer cells, but an “army” of T cells is required to eliminate a tumor. In “hot” tumors, where T-cell infiltration is high, PD1 inhibitors are sufficient to unleash pre-existing T cell’s ability to kill cancer cells. However, most TNBC tumors tend be “cold,” with low T-cell infiltration. The combination of radiation therapy and CTLA-4 inhibitors activates T cells and drives them into the tumor, but this “army” is still too small to do the job.
Although T cells express many inhibitory receptors, targeting them did not further improve T-cell’s ability to fight the cancer. We soon realized that we needed to focus on the T-cell’s partners, the myeloid cells, to increase the immune response.
— Dr. Sandra Demaria
“The goal of our study was to identify a way to boost the number and activation of the T cells and achieve responses in most if not all TNBC tumor-bearing hosts,” says Dr. Demaria. “Although T cells express many inhibitory receptors, targeting them did not improve T-cell’s ability to fight the cancer. We soon realized that we needed to focus on the T-cell’s partners, the myeloid cells, to increase the immune response. We know myeloid cells in the TME get educated by the breast cancer cells to be immunosuppressive. We needed to find a way to interfere with that process.”
The Role of CD40 Agonists in “Cold” TNBC
In the study, the researchers conducted an analysis of the TME in immunotherapy-refractory TNBC mouse models to identify avenues that would enhance the immune response. Their analysis revealed that radiation treatment plus CTLA-4 inhibitor increased the activation and number of T-cells in the TME. However, only a minority of the treated mice showed tumor regression. After analyzing the data for other potential targets, the researchers discovered that adding CD40 agonist, an antibody that stimulates dendritic cells, increased the “killer” CD8 T-cell activity in the TME, thereby significantly improving response rates.
The researchers concluded that treating “cold” tumors such as TNBC with a combination of radiation therapy, CTLA-4 inhibitors and CD40 agonist may be more effective than therapies that target only T-cell checkpoints.
For Dr. Demaria, continued research into the TME and its various immune cell compartments is critical for the development of treatments that are effective for all TNBC patients. “The goal of improving therapy for TNBC is to benefit everyone, yet there are big differences in patients’ tumors and their TMEs,” she adds. “We need to identify the optimal treatment approach for each individual patient. The degree of lymphocytic infiltration in the TME is useful as a biomarker of an immunogenic tumor that every breast cancer pathologist can assess without complicated, sophisticated and expensive tests, and we are going to include this evaluation in our reports for TNBC. However, this is just the first step towards incorporating the assessment of the TME as a critical component of every tumor, one that can help tailor treatment”.
Soon, the triple-combination radiation, CTLA-4 inhibitor and CD40 agonist therapy will be explored in a clinical trial of TNBC breast cancer patients. “I am quite excited about testing this combination in a clinical trial because I believe there will be a subset of patients currently not benefitting from treatment that can achieve a response,” says Dr. Demaria. “One of our research goals is to explore the possibility of delivering immunotherapy where it matters the most, inside the tumor, and not systemically, to reduce the risk of toxicity in patients. Additionally, we want to increase overall response to this therapy. Right now, 10-20% of mice show good response with radiation and CTLA4 inhibition, and when we add CD40 agonist, we get 60-70% response, but we have not yet achieved 100% response.”
Weill Cornell Medicine has a flourishing cancer center with great talent and a vision for how to promote translational research in immunotherapy. Moreover, there is a lot of interest at Weill Cornell in personalizing treatments so that patients of all backgrounds and ethnicities can benefit equally.
— Dr. Sandra Demaria
Working alongside her colleagues at NewYork-Presbyterian/
“Right now, there is much interest in expanding treatments so that patients of all backgrounds and ethnicities will benefit,” she continues. “Most breast cancer clinical studies are conducted in Europe and the U.S., and women of different genetic ancestry are not equally represented. However, peoples’ immune systems are shaped by infectious diseases where their ancestors lived. When we design a clinical trial for a breast cancer immunotherapy, we need to keep in mind and understand potential differences in the immune system of women of different genetic ancestry .”
Since TNBC occurs so frequently in patients of African American descent, it's important to know whether their immune environments are the same as in Caucasian patients, which comprise most of the data we have obtained so far for the study of TNBC. This area of inquiry is very exciting to me, and it takes a village to address these questions; we are fortunate to have Dr. Lisa Newman at NewYork-Presbyterian/Weill Cornell Medicine who is a pioneer in this area of investigation.
— Dr. Sandra Demaria
“Since TNBC occurs so frequently in patients of African American descent, it's important to know whether their immune environments are the same as in Caucasian patients, which comprise most of the data we have obtained so far for the study of TNBC,” she says. “This area of inquiry is very exciting to me, and it takes a village to address these questions; we are fortunate to have Dr. Lisa Newman at NewYork-Presbyterian/
