Study Explains Why Anti-CTLA-4 Immunotherapy Has a Spectrum of Efficacy in Cancer Patients

The immunotherapy drug ipilimumab (Yervoy) is a monoclonal antibody against CTLA-4 that is approved for treatment of metastatic melanoma patients. Some cancer patients respond well and have durable long-term remission after treatment with the immunotherapy, while some patients do not respond at all. A large research effort among oncologists and immunologists has been to understand why this immunotherapy and others works very well in some patients and not so well in others.

A new study by Edward Cha, MD, of the Helen Diller Family Comprehensive Cancer Center in San Francisco, and colleagues are hoping to illuminate as to why the immunotherapy antibody that works by boosting patients’ immune systems is successful in some, but not in others. The researchers found that the anti-cytotoxic T lymphocyte–associated antigen-4 (CTLA-4) antibody works best in those patients who already have a population of immune cells called T-cells and after completion of 3 months of therapy. It appears that anti-CTLA-4 therapy, when it works, helps to maintain the T-cell response that already exists.

The study has implications of how other novel cancer immunotherapies in development such as, the anti-Programmed Death Receptor 1 (PD-1) and anti-Programmed Death Receptor Ligand 1 (PD-L1), function to boost the immune system against cancer and their differential responses among cancer patients.

CTLA-4 antibodies promote an anti-tumor response by facilitating T-cell activation and persistence; although the exact mechanism of action is not fully clear. CTLA-4 is a co-inhibitory receptor on T-cells that facilitates control of T-cell activation both during the initiation and the maintenance phases of adaptive immune responses.

The researchers further addressed the mechanism of anti-CTLA-4 antibodies by using next-generation sequencing to measure rearranged T-cell receptor beta genes from patient samples.  This was done in order to characterize the spectrum of different types of possible rearrangements within the same patient.

Twenty-five metastatic castration-resistant prostate cancer patients treated with a range of ipilimumab doses and GM-CSF as part of a phase 1/2 clinical trial, 21 metastatic melanoma patients treated with tremelimumab (another anti-CTLA-4 antibody), as part of a monotherapy phase 1 clinical trial, and nine untreated control participants took part in the study. Both the clonal populations and survival were compared among the two different cohorts and the untreated control group. The T-cell sequencing and clonal analysis was done using the LymphoSIGHT system from Sequenta Inc., an immune repertoire sequencing platform.

The study showed that those patients who had a clinical response to therapy had a higher frequency of T-cell receptor clone cells prior to the start of therapy and maintained the frequency of these clones. In contrast, the frequency of the clonal cells decreased with treatment among patients who had short overall survival. CTLA-4 therapy boosts the diversity of T-cell receptors which continued to evolve throughout the months of treatment, although the number of different clones per patient did not correlate with outcomes, the authors concluded.

Monitoring the baseline and changes in T-cell clones of patients is likely to help identify a subpopulation of patients who are most likely to respond to anti-CTLA-4 therapy. About 10% to 15% of patients treated with ipilimumab respond to therapy according to results of randomized phase 3 metastatic melanoma trials. But, as many as one-quarter of the patients who do respond, survive for 3 to 10 years, according to a 2013 longer-term follow up study of melanoma patients presented at the European Cancer Congress 2013.

Still, as the authors highlight, larger sample sizes and prospective trials are needed to validate whether monitoring T-cell clonal types is a potential prognostic or predictive biomarker for CTLA-4 or other immunotherapies.