F. Stephen Hodi, MD
Director, Melanoma Center
Director, Center for Immuno-Oncology
Dana-Farber Cancer Institute
The concept of manipulating the immune system to treat cancer has experienced waxing and waning levels of enthusiasm over decades of clinical investigation. With improved understanding of how the immune system functions, harnessing the power of T-cell checkpoint antagonists has dramatically changed this prospect and shifted a paradigm of cancer care.
The primary interaction in educating the immune system occurs between the professional antigen-presenting cell (APC) (eg, dendritic cell or B cell) and the T cell. The APC functions to process antigen proteins into peptides, which are presented on its cell surface within the groove of the major histocompatibility complex (MHC). The peptide is presented to the T cell via interaction with the T-cell receptor (TCR). For T cells to gain potency against the antigenic peptide, B7 on the APC side and CD28 on the T-cell side must interact, resulting in costimulation. The T cell proliferates and makes cytokines such as interleukin-2 in its immunologic capacity. If this proceeded unchecked, it would result in nonspecific reactivity or autoimmunity. Therefore, upon activation of the T cell, cytotoxic T-lymphocyte antigen-4 (CTLA-4) is expressed on the T-cell surface, which has greater binding affinity to B7 than CD28, resulting in T-cell inhibition.
Ipilimumab Data Demonstrate Benefit
In a randomized phase III trial involving previously treated patients with melanoma including treated brain metastases, ipilimumab, a fully human CTLA-4 blocking antibody administered at 3 mg/kg for 4 doses, demonstrated an improvement in survival when combined with a gp100 peptide vaccine or as a single agent when compared with the vaccine alone.1
Importantly, the significant benefit was witnessed in the tail of the Kaplan-Meier curve, demonstrating durable survival in a subset of patients. This led to the FDA approval of ipilimumab for the treatment of metastatic melanoma. Ipilimumab benefit was confirmed in a subsequent phase III trial in patients with treatment-naïve melanoma. Ipilimumab (10 mg/kg x 4 doses, plus maintenance every 3 months) combined with dacarbazine chemotherapy (850 mg/m2) demonstrated an improvement in overall survival compared with dacarbazine alone.2
Activity for ipilimumab has also been reported in a number of other cancers, including renal cell carcinoma (RCC), non–small cell lung carcinoma (NSCLC), and prostate cancer.
Unique Inflammatory Events Surface
The development of ipilimumab revealed a unique set of inflammatory adverse events (AEs). Dermatitis is the most common AE, seen in approximately 40% of patients. Fortunately, this is typically low grade and commonly does not need medical intervention. Diarrhea/ colitis can be seen in approximately 30% of patients (high-grade, about 8%). The concern with patients experiencing high-grade or prolonged diarrhea is development of bowel perforation, as deaths have been associated with treatment. Other potential inflammatory AEs include endocrinopathies (hypophysitis and thyroiditis), hepatitis, pancreatitis, nephritis, uveitis, and neuritis. Algorithms have been developed to assist in the management of these side effects, with particular attention to diarrhea and liver function toxicities.
PD-1/PD-L1 Inhibitors Stir Interest
T cells that are activated to seek and destroy cells expressing a specific MHC-bound peptide express on their surface the programmed death-1 (PD-1) receptor. When other cells, such as tumor cells, express the ligand (PD-L1), the PD-1/PD-L1 interaction leads to apoptosis of activated lymphocytes.3,4
As a result, the tumor cells—via expression of PD-L1—can ward off an immune attack by placing a cloak around themselves or stiff-arming the immune system. The expression of PD-L1 (also referred to as B7H1) is significant in a wide variety of tumors, including melanoma and RCC.5
For some cancers, such as RCC, expression of PD-L1 has been associated with poor prognosis. Currently, there are no fewer than 7 companies developing antagonistic antibodies to PD-1 or PD-L1.