A new study published in the New England Journal of Medicine has identified a mechanism that may explain why ipilimumab controls melanoma in only some people. The study also provides new important insights on the identity of molecules, on the surface of cancer cells, which allow the body’s immune system to identify and destroy them.
Memorial Sloan Kettering scientists played a major role in the development of ipilimumab, which works by blocking a protein called CTLA-4. Normally, CTLA-4 keeps the tumor-fighting activity of the immune system’s T cells in check. In the presence of the drug, T cells are unleashed and their inherent ability to recognize and destroy cancer cells is enhanced.
The fully human monoclonal antibodies ipilimumab and tremelimumab block cytotoxic T-lymphocyte antigen 4 (CTLA-4), resulting in T-cell activation.
Ipilimumab (YervoyTM), a drug that boosts the body’s natural immune defense against tumors has shown promising results in some patients with melanoma. But immunotherapy doesn’t help everyone. In fact, about 80 percent of people with melanoma get little or no benefit from ipilimumab. And thus far, doctors have had no way of predicting which patients are more likely to respond to the drug.
Thus, the factors determining whether a patient will have a response remain elusive. Moreover, the relationship among the genomic landscape of the tumor, the mutational load, and the benefit from treatment remains obscure.
It is known that effector and helper T-cell function and regulatory T-cell depletion are necessary for the efficacy of CTLA-4 blockade, but there is not an association between a specific HLA type and a clinical benefit. Melanomas have very high mutational burdens (0.5 to >100 mutations per megabase) as compared with other solid tumors. Elegant studies have shown that somatic mutations can give rise to neoepitopes and that these may serve as neoantigens.
In the New England Journal of Medicine study Alexandra Snyder and colleagues from the Memorial Sloan Kettering Cancer Centre in New York investigated whether the genetic landscape of a tumor affects the clinical benefit provided by CTLA-4 blocking agents.
In the study, the researchers collected tumor samples from 64 melanoma patients who had been treated with ipilimumab or tremelimumab, an experimental drug that works in a similar way. The tumors were analyzed by whole-exome sequencing, a method of deciphering DNA changes across all parts of the genome that code for protein. About half of the tumors analyzed came from patients for whom the treatment had been successful and the other half from people who derived little or no benefit from it.
In this study the investigators found that drug-responsive tumors share a certain type of mutation that makes cancer cells express new antigens — substances that T cells can detect and recognize as foreign to the body.
As discussed by the authors – it is well known in the field of infectious diseases that an individual amino acid within a peptide can affect immunogenicity by altering peptide–MHC or peptide–T-cell receptor interactions. In cancers, the altered amino acid residue resulting from a single missense mutation can create a T-cell epitope from a previously self-peptide. In the patients described here, altered amino acids resulting from tumor mutations caused the tumors to display somatic neoepitopes that elicited an antitumor response augmented by CTLA-4 blockade.
“We identified a specific subset of tumor antigens found only in patients who respond well to CTLA-4 blockade therapy,” says Dr. Chan, the senior author of this study. The researchers believe these mutations make tumors express the new antigens that the immune system then reacts to — and ipilimumab works by enhancing that reactivity.
As reported by Cancer Research UK, Dr. Sergio Quezada, from the UCL, London believes that this is a “a huge breakthrough” and the researchers have “actually discovered molecular motifs that will inform the development of the next generation of therapies”.
Source: N Engl J Med, 2014 Nov 19. [Epub ahead of print]