Cytotoxic T-lymphocyte-associated Protein 4 and Cancer Therapy

The existence of multiple non-redundant l inhibitory pathways that limit T cell responses offers novel strategies for mobilizing the immune system to attack cancer cells. The best characterized of these immune checkpoints is CTLA-4, which inhibits CD28 mediated costimulation. Antibodies to CTLA-4 have proven effective against multiple tumor types in both pre-clinical and clinical studies. Ipilimumab, an antibody to human CTLA-4, showed long term (>4.5 years) survival benefit in about 23% of patients in a randomized, placebo-controlled trial in late stage melanoma. In 2011 it was approved by the FDA for treatment of late stage melanoma and is now a standard of care for that disease. A recent retrospective study of almost 5,000 patients showed an inflection point at about 2.5 years with essentially no deaths of about 20% of patients for 10 years following treatment.

The mechanism(s) of action of anti-CTLA-4 are still being elucidated. We and others have shown that CLTA-4 limits T cell proliferation by a cell intrinsic mechanism. However, there is also evidence that anti-CTLA-4 has to engage the target on both effector (Teff) and regulatory (Treg) T cells. We have recently uncovered a mechanism whereby anti-CTLA-4 antibodies expand Treg in lymph nodes but cause their depletion in the tumor microenvironment. Thus anti-CTLA-4 exerts its anti-tumor effects by multiple mechanisms. We have also shown that CTLA-4 blockade results in a 2-5 fold increase in the frequency of CD4 T cells expression ICOS (inducible costimulator) in both tumor tissues and blood. This population contains that vast majority of tumor antigen specific cells that produce IFNg and TNFa. The appearance of the ICOS+ CD4 cells serves as a pharmacodynamic marker of a biological effect of anti-CTLA-4 activity. Using mouse models, we have shown that the ICOS/ICOSL pathway is critical for optimal anti-tumor activity of anti-CTLA-4. Furthermore, we have shown that agonist stimulation of ICOS coupled with CTLA-4 blockade results in enhanced anti-tumor efficacy in mouse models, suggest that ICOS is a compelling molecule to develop as a target for agonistic targeting of costimulatory checkpoints.

PD-1, another checkpoint, recruits a phosphatase and seems to interfere with T cell antigen receptor mediated signaling. It has two ligands, PD-L1 and PD-L2, which are both expressed on dendritic cells. However, many tumor cells also express PD-L1. Antibodies to PD-1 and PD-L1 have both shown objective responses against several tumor types in clinical trials with response rates of about 25% . A recent phase II trial of a combination of anti-PD-1 and anti-CTLA-4 in melanoma showed objective responses in about 50% of late stage melanoma patients. Our studies indicate that the mechanisms of anti-PD-1 mediated tumor immunity are distinct from those of anti-CTLA-4, at least as for the role of ICOS+ CD4 T cells.

These studies and their implications for cancer therapy will be discussed.