As we've discussed previously on the blog, bio-pharmaceutical entities are scrambling to bring new immunotherapies to the clinic, particularly in the treatment of cancers. The US Food and Drug Administration (FDA) and other regulatory agencies worldwide have already approved several immunotherapies for the treatment of various tumors, including melanoma and non-small cell lung carcinoma (NSCLC). However, pre-clinical and clinical trials to assess the safety and efficacy of investigational immunotherapies for breast cancer have only recently begun.
The Rise of Immunosurveillance for Cancer Treatment
The cancer researchers and oncologists have experienced a significant paradigm shift over the past decade as the evidence that cancers are immunogenic continues to build. Classically, cancer has been understood and approached as a disease caused by genotypically mutant cells which have acquired the ability to replicate seemingly uncontrollably. The rogue malignant cells would evade inhibitory signals to invade nearby tissues, and then metastasize to distant sites. Accordingly, cancer treatments were developed to specifically target the vulnerabilities of malignant cells.
The view of cancer as a cell-autonomous disease has expanded to accommodate the concept that malignant cells are under immunosurveillance and are susceptible to attack by the body’s natural immune response. A cancer, then, would only thrive if the malignant cells evade immune recognition or if a tumor microenvironment which can suppress the immune response is created. The failure of the immune response to eliminate the malignant cells and nascent tumors results in the uncontrolled progression of the cancer.
As a result of the mounting evidence that cancers are immunogenic, the field has experienced an emergence of immunotherapies. These include therapies that stimulate immune signaling pathways as well as ones that block immunological checkpoints. Of particular interest are therapies that use the patients’ own immune system to re-instate suppression of neoplastic cells. A substantial body of research now supports the viability of the immunosurveillance model and the active search for new treatments—including for breast cancer.
Re-Thinking Traditional Therapies
Over the past five years, the FDA has approved several therapies which exploit immune pathways to target several cancer types including prostate, melanoma and malignant NSCLC. A robust body of literature provides strong evidence that breast cancers also elicit a host immune response and therefore immunotherapy may also prove to be successful against breast cancer.
Indeed, improved prognosis of breast cancer patients is directly correlated with signs of an active immune response against malignant cells. The immune activity, such as the levels of tumor infiltrating leukocytes, at the time of diagnosis implicates the potential success of immunotherapy and can help guide clinical decisions.
Furthermore, the efficacy of trastuzumab (or Herceptin, a common therapy for certain types of breast cancer) was originally attributed to its ability to interfere with the HER2 receptor, therefore limiting cell growth and division of the cancer cell. There is however strong evidence that the innate and adaptive arms of the immune system are involved in the mechanism of action of trastuzumab as well as of other targeted anticancer therapeutics. In the case of trastuzumab, the presence of several key immune cell types (CD8+ and CD4+ T cells) results in the optimal therapeutic efficacy in mouse models.
Therapies which block immunological checkpoints are providing data that may lead to additional immunotherapy options for breast cancer patients. Therapies using monoclonal antibodies against the T-cell inhibitory molecule PD-1 or its ligand, programmed cell death receptor 1 ligand (PD-L1) for example can produce therapeutic effects in triple negative breast cancer (TNBC) patients.
Going forward the field will continue to explore other forms of immunotherapy, such as adoptive cell transfer. In this innovative therapy, a patient’s own tumor-reactive T-cells are expanded and activated ex vivo then transferred back to the patient. There are currently several adoptive cell therapy strategies targeting breast cancer in various phases of clinical trials which the field is following closely.
To learn more about the important variables to consider if you have a cell-based therapy in development and the unique logistical challenges associated with autologous cell therapies, please download our eBook Cell Therapy Logistics: Beyond the Basics.