Cancer Immunotherapy, Yesterday and Today

Immunotherapy is making a comeback in the treatment of cancer. What will that mean for breast cancer patients?

As Cancer Immunotherapy Month passes, BCRF reviews the history of cancer immunotherapy, its recent advancements and its role in breast cancer treatment.

The immune system is the body’s natural defense against foreign pathogens. Under normal conditions, the immune system works through a coordination of on and off switches that identify and destroy diseased and abnormal cells. Defects in the on/off switches can result in immune-related diseases where the immune system fails to recognize pathogens as foreign (e.g. HIV-AIDS) or where the immune system fails to recognize normal cells as “self” and launches an inappropriate attack on healthy systems (e.g. rheumatoid arthritis). Likewise, when normal cells mutate to become cancerous they may appear different from normal cells and activate an immune response. Conversely, cancer cells may disguise themselves and go undetected or deactivate the immune system to block an immune response.

What is Cancer Immunotherapy?

At its simplest, cancer immunotherapy involves harnessing a patient’s immune system to attack cancer cells. Scientists have known for more than a century that the immune system can detect and kill cancer cells, but successful cancer immunotherapy has been elusive for patients. An explosion of research more recently has increased our understanding of immune- and tumor-cell biology and unveiled potential ways to unmask tumor cells and make them visible to the immune system. Major discoveries in immune-targeted therapies are leading the way in a new era of cancer immunotherapy and clinical trials are ongoing in different cancer types including breast cancer.

Where is Cancer Immunotherapy Today?

There are several immune-based strategies being pursued as potential anti-cancer therapies. These include cancer vaccines, adoptive cell transfer, and drugs that modulate the immune system.

• Cancer vaccines are designed to prevent cancer from developing, or to strengthen the immune system to increase its efficacy in recognizing and killing cancer cells.
  • In 2010 the FDA approved the first cancer vaccine, Sipuleucel-T (Provenge) for treatment of advanced prostate cancer. The vaccine stimulates the immune system to target a protein expressed on prostate cancer cells.
• Adoptive cell therapy involves removing immune cells from a patient, genetically or chemically re-engineering them to enhance their anti-tumor activity, and re-introducing them back into the patient.
  • A new trial is using advanced gene-editing technologies to modify T-cells to boost their anti-cancer killing efficiency of cancer in patients with myeloma, sarcoma, or melanoma who have stopped responding to existing treatments.
• Immune checkpoint therapy restores the normal immune response by preventing tumor cells from shutting it down. Two targets of this therapy are:
  • PDL-1/ PD-1. Tumor cells increase these proteins to dampen immune response. Monoclonal antibodies to block PDL-1/PD-1 interaction have shown success in lung cancer and other cancer types.
  • CTLA-4. This protein also acts to put the brakes on the immune system. Targeted anti-CTLA-4 therapies have shown promise in patients advanced melanoma. 

Immunotherapy for Breast Cancer

The success of immunotherapy in melanoma, lung and other cancers has spurred interest in pursuing these strategies in breast cancer. In fact, some recent studies have demonstrated that in addition to blocking the HER2 receptor to prevent growth of cancer cells, trastuzumab (FDA approved in 1998 for the treatment of HER2+ breast cancer) also recruits immune cells to attack the cancer cells. BCRF investigator Sherene Loi has shown that a better immune response is associated with better outcomes. A new clinical trial co-chaired by Dr. Loi is currently underway. Other trials include:

• A phase Ib/II trial (NCT02129556) evaluating the efficacy of targeting PD-1 with a new drug, MK-3475) in combination with trastuzumab in patients with trastuzumab-resistant, HER2-positive metastatic breast cancer. This study is currently recruiting patients and primary outcome results are expected by December 2017.
• BCRF investigator, Leisha Emens is the principal investigator of a phase II study (NCT00399529) to assess the safety, clinical benefit, and bioactivity of the cancer vaccine GM-CSF in combination with other drugs in HER2-positive metastatic breast cancer. Study results published in 2014 showed a clinical benefit rate at six months and one year was 55 percent and 40 percent respectively. Median progression-free survival (PFS) and overall survival (OS) were 7 and 42 months respectively.

BCRF has been at the vanguard in breast cancer research since its founding 23 years ago and its commitment to fund innovative research. As a result, BCRF has played a role in every major clinical advancement in breast cancer. With the re-emergence of immunotherapy as a viable treatment for cancer, BCRF investigators are pursuing innovative research and clinical trials to explore its potential for breast cancer patients.

Last year, BCRF invested $6.5 million in immunology-related projects including studies to identify immune biomarkers that can ultimately be used to predict treatment response and new targeted and combination therapies that will hopefully lead to better outcomes in breast cancer. In addition to those mentioned above, BCRF investigators leading the way in this work include Karen Anderson, Susan Domchek,  Elizabeth Jaffee,  Annette Khaled, Silvia Formenti, Sandra Demaria, and Robert Vonderheide.