Expanding the Frontiers of Breast Cancer Immunotherapy

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Elizabeth A. Mittendorf, MD, PhD, a breast cancer surgeon and international leader in breast cancer vaccines, recently joined Brigham and Women’s Hospital (BWH) from the MD Anderson Cancer Center in Houston, where her research focused on vaccines that target the HER2 protein expressed on many breast tumors. At the Brigham, her work focuses on advancing our understanding of breast cancer immunotherapies.

As the Director of the Breast Cancer Immuno-Oncology Program at the Dana-Farber/Brigham and Women’s Cancer Center (DF/BWCC), Dr. Mittendorf oversees basic research that investigates the biology of breast cancer and its interaction with the immune system and leads clinical research that evaluates immunotherapy agents against breast cancer. 

“We hope to build the Breast Cancer Immuno-Oncology Program into one of the preeminent programs in the country,” said Dr. Mittendorf, who has brought together clinical trialists, cancer surgeons, radiation oncologists, and medical oncologists with basic researchers and physician-scientists who study breast cancer. 

A collaboration has been established with Sandra McAllister, PhD, of the Brigham’s Hematology Division, to investigate the impact of age on response to immunotherapy in breast cancer patients.     

Making breast tumors immunogenic with combination therapies 

“While there are data to suggest that breast tumors have less of a T-cell infiltrate, there’s growing evidence to signal that breast tumors can be made more immunogenic and responsive to various immunotherapy agents,” said Dr. Mittendorf.     

At the Miami Breast Cancer Conference in March of 2018, Dr. Mittendorf summarized data from clinical trials reported in 2017 that examined immune checkpoint blockade agents as monotherapy. The response rate to this treatment was roughly 10 percent.

The field can do better than 10 percent, noted Dr. Mittendorf, by making tumors more immunogenic and susceptible to checkpoint blockade agents through the use of combination strategies. One strategy has been to combine a checkpoint blockade with chemotherapy agents, an approach that’s being investigated in several clinical trials. 

For example, the IMpassion130 trial, a Phase III trial, investigated the anti-PD-L1 antibody atezolizumab with chemotherapy in patients with metastatic triple negative breast cancer. The results were presented at the ESMO meeting in October 2018. 

Highlights of the IMpassion130 trial

The IMpassion130 trial enrolled about 900 patients with metastatic tNBC being treated with either atezolizumab + nab-palitaxel or placebo + nab-paclitaxel. 

The patients who received atezolizumab showed an improvement in their progression-free survival (PFS); the improvement was greatest in patients with PD-L1 expression on cells in the tumor microenvironment (“PD-L1+ tumors”). 

Although formal statistical testing was not conducted on the overall survival results, patients with PD-L1+ tumors showed an improvement in OS from 15 months for the placebo patients to 25 months for the atezolizumab patients.   

“This means that the combination of the immunotherapeutic agent atezolizumab with the chemotherapy leads to improved PFS in metastatic triple negative breast cancer. It’s estimated that the IMpassion130 trial will lead to an FDA approval and a change in standard of care therapy for metastatic triple negative breast cancer,” said Dr. Mittendorf.  

Dr. Mittendorf is engaged in several clinical trials that use chemotherapies in combination with checkpoint blockade agents to stimulate an immune response in a pre-surgical setting. She’s principal investigator for an international study where atezolizumab is being used in combination with chemotherapy in patients with earlier stage disease. 

In another study, led by colleagues at DF/BWCC, Adrienne Gropper Waks, MD, and Sara Michell Tolaney, MD, Dr. Mittendorf and the team of investigators are evaluating the anti-PD-1 antibody pembrolizumab in combination with the chemotherapeutic agent nab-paclitaxel in patients with hormone receptor positive breast cancer. 

Vaccine for HER2-positive breast cancer 

Dr. Mittendorf and her colleagues recently published data demonstrating a potential mechanism of synergy between a HER2-targeting vaccine (NeuVax) in combination with trastuzumab, a monoclonal antibody that targets the HER2 protein. 

She is leading two Phase II trials that examine the combination of vaccine plus trastuzumab. Both trials administer the combination therapy in women who have been rendered disease-free with standard of care therapies but are at a high risk for recurrence.  

“One trial of 275 women has shown compelling interim data suggesting that patients who have hormone-receptor negative tumors with low HER-2 expression may benefit significantly,” said Dr. Mittendorf, who is moving forward with a confirmatory study given the interim analysis. These data were presented at the ESMO conference in in Germany in October 2018.

She and her colleagues at DF/BWCC are also investigating the use of vaccines in the earliest disease stages as an initial step towards developing a truly preventative vaccine therapy. A trial being led by Dr. Mittendorf is vaccinating women with Stage 0 breast cancer (ductal carcinoma in situ) prior to their operation. If this approach produces an immune response, it could be used early as a preventative therapy. This study is accruing patients at DF/BWCC, MD Anderson in Houston, and Thomas Jefferson University. 

Injecting immunotherapeutic agents into tumors

In collaboration with Brigham breast surgeon Thanh U. Barbie, MD, Dr. Mittendorf is also investigating the injection of immunotherapeutic agents directly into tumors, including the STING (stimulator of interferon genes) agonist.   

“Dr. Barbie is investigating the mechanisms by which the STING agonist works and strategies to make it more effective, including ways to make it remain in the local tumor environment longer,” said Dr. Mittendorf. 

Since these intralesional agents haven’t typically been used to treat breast cancer, Dr. Mittendorf sees an opportunity for the team at BWH/DFCI to lead the field. She and Dr. Barbie hope to study the intra-tumor injection of STING agonists as well as other immunotherapeutic agents, such as TLR7/8 agonists and oncolytic viruses.     

In addition to injecting these agents directly into tumors, investigators within the Breast Cancer Immuno-Oncology Program are investigating novel delivery systems to address the challenge of controlling the release of the drugs into the tumor environment.  

Addressing the tumor microenvironment

“Even if we are successful in stimulating T cells to recognize breast tumor cells, when those T cells enter the tumor microenvironment they are often confronted by other immune cells that can hamper T cells’ ability to kill off the tumor,” said Dr. Mittendorf.  

Jennifer Guerriero, PhD, an expert in the field of tumor macrophages and Director of the Breast Tumor Immunology Lab, is working with Dr. Mittendorf to better understand the tumor microenvironment.     

“We are currently completing studies that examine ways to either target and eliminate these macrophages or reprogram them from being pro-tumor to anti-tumor. We are optimistic that these studies will lead to clinical trials soon,” said Dr. Mittendorf.  

To learn more about the Breast Cancer Immuno-Oncology Program, please call (617) 582-9980. To enroll a patient in an immunotherapy clinical trial, please contact Jennifer Savoie, Associate Director of Clinical Research, at (617) 632-4241, or Jennifer_Savoie@dfci.harvard.edu.

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