By: Matthew Biancalana
Antibodies are the immune system’s targeted defense system, known best for their ability to selectively pinpoint pathogens and mark them for destruction. The last decade in cancer care has been defined by the rapid emergence (and in some cases, dominance), of monoclonal antibody therapies, where they serve as a critical foundation of oncologic care.
There are two different immunotherapy approaches for directing cancer cell destruction. These strategies form the core of immuno-oncology (IO) care:
- Targeting proteins that are either mutated or overexpressed on the surface of cancer cells. Therapeutic antibodies targeting specific proteins associated with cancer include trastuzumab, which binds to the HER2 receptor that is overexpressed on the surface of certain breast cancer subtypes. HER2-targeting antibodies function by “flagging” the cancer cell for destruction by a variety of immune cells, most notably T cells.
- Utilizing immune checkpoint inhibitor (ICI) antibodies, which selectively enable the body’s immune system to target and attack cancer cells. ICIs function by “removing the brakes” from immune cells and allowing them to target cancer cells. Cancer cells still possess many features of normal cells, and may therefore not otherwise trigger an immune response unless the body’s innate “checkpoints” are dampened. The best-studied ICI target disrupts the interaction between the inhibitory cell surface receptor PD-1 (programmed cell death protein 1) on T cells, and the binding partner PD-L1 (programmed cell death protein ligand 1) on cancer cells. Cancers often upregulate PD-L1 as a mechanism to prevent destruction by routine immune cell surveillance. However, blocking the PD-1/PD-L1 interaction using antibodies that bind to either PD-1 (pembrolizumab, nivolumab) or PD-L1 (durvalumab, atezolizumab) inhibits the activity of the PD-1/PD-L1 checkpoint, and allows the T cell to attack the tumor.
Both of these approaches form the cornerstone of modern IO therapy. In addition to the PD-1/PD-L1 pathway (currently the most widely-targeted pathway in ICI therapy), the IO field features a growing range of targets driving the latest surge in research. The range of receptor-ligand interactions targeting related inhibitory interactions includes pathways such as CTLA-4/CD-80 and TIM3/Gal9, each of which reflects a binding interaction between proteins on the surface of a T cell and a corresponding protein on the surface of a tumor cell, respectively. The identification of new checkpoint interactions continues to offer further avenues for therapeutic investigation.
Among cancer types, IO therapies are particularly useful for the skin cancer melanoma, as well as several subtypes of breast cancer. ICI has shown remarkable efficacy among triple negative breast cancer (TNBC) tumors, both in the context of early-stage disease as well as advanced tumors that have spread (metastasized) to other parts of the body. TNBC tumors often have a so-called high mutational burden – that is, the cancer cells have acquired numerous mutations, including errors in genes encoding for genetic repair machinery. Loss of these genetic proofreading mechanisms makes TNBC tumors far more likely to acquire additional mutations as they continue to grow.
These characteristics simultaneously make TNBC particularly dangerous and aggressive, due to its rapid ability to mutate and adapt to many types of therapies. However, TNBC is also highly responsive to ICI therapy, as compared to other classes of breast cancer with fewer wide-spread genetic mutations. Recent results from the KEYNOTE-522 trial of the ICI antibody pembrolizumab in early-stage breast cancer, in addition to background chemotherapy, demonstrates improved long-term survival outcomes. ICI therapy now comprises one of the foundational first-line therapies given at the time of cancer diagnosis for highly genetically-mutated cancers such as melanoma and TNBC.
Although effective as isolated “monotherapies,” treatment with a combination of ICIs can also be used to generate even stronger immune responses and improved therapy outcomes. Recent trials have begun to query the application of multiple ICI therapies to see if the effects of previous standard-of-care monotherapies can be enhanced.
The recent BELLINI trial examined the responsiveness of TNBC patients to ICI based on a combination of nivolumab (a PD-1 blocking antibody) and ipilimumab (a CTLA-4 blocking antibody). In particular, researchers aimed to dissect responsiveness as a function of the amount of tumor-infiltrating lymphocytes (TILs) (immune cells that reside within the tumor) at baseline. The majority of TNBC patients with high levels of TILs showed increased immune response after only 4 weeks of combination ICI. These results highlight the potential of ICI therapy for TNBC, even without chemotherapy.
IO and ICI therapies are key therapeutic strategies within the breast cancer field. Read further details about how SimBioSys technologies are advancing immune targeting of tumors: https://jitc.bmj.com/content/10/Suppl_2/A134