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Melanoma tumor genetics determined clinical benefit from CTLA-4 blockades
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The presence of somatic neo-epitopes was associated with prolonged clinical benefit from CTLA-4 blockades in patients with melanoma, according to study results.
High mutational burden also was associated with — but did not independently predict — clinical benefit from the cytotoxic T-lymphocyte antigen 4 (CTLA-4) blockades ipilimumab (Yervoy, Bristol-Myers Squibb) and tremelimumab (CP-675,206; Pfizer, Debiopharm), results showed.
Alexandra Snyder, MD, fellow in the human oncology and pathogenesis program at Memorial Sloan Kettering Cancer Center, and colleagues used massively parallel sequencing to evaluate malignant melanoma exomes from 64 patients. All patients had been treated with an anti-CTLA–4 agent.
Researchers first evaluated genomic data from a discovery set comprised of 11 patients who had achieved long-term clinical benefit from a CTLA-4 blockade — defined by freedom from disease, stable disease or decreased disease volume for more than 6 months — and 14 patients who demonstrated minimal or no benefit with anti-CTLA–4 therapy.
The mutational load was significantly different between patients who did and did not demonstrate long-term clinical benefit (
However, researchers noted some patients with high mutational loads did not respond to treatment and, therefore, mutational load alone did not predict survival benefit.
Researchers then used data on prediction of major histocompatibility complex (MHC) class I binding, modeling of T-cell receptor binding, patient-specific HLA type and an epitope-homology analysis to identify neo-epitopes generated from somatic mutations in each patient.
From this analysis, researchers created a predictive signature of candidate neo-epitopes that included 101 tetrapeptides exhibited only in patients who had demonstrated a long-term clinical benefit to anti-CTLA–4 therapy.
The analysis also included a validation cohort of 39 patients, 25 of whom had experienced a long-term clinical benefit from a CTLA-4 blockade. The neo-epitope signature was significantly associated with survival in the discovery and validation cohorts (
“Our use of whole-exome sequencing to identify a genetic basis associated with a benefit from CTLA-4 blockade provides proof of principle that tumor genomics can inform responses to immunotherapy,” Snyder and colleagues wrote. “For the field of cancer genetics, these data suggest a need for an expanded definition of the previous categories of driver and passenger mutations. Our data show that exonic missense mutations in general confer increased MHC class I binding and confirm the hypothesis that some mutations formerly categorized as passengers may in fact represent ‘immune determinants.’”
These results suggest that anti-CTLA–4 agents require T cell activation, Vassiliki A. Boussiotis, MD, PhD, professor in the department of medicine at Harvard Medicine School and the Beth Israel Deaconess Medical Center, wrote in an accompanying editorial.
“It is conceivable that — in patients with melanomas expressing immunogenic neo-epitopes — mutant peptides capable of binding MHC class I molecules with high affinity induce T-cell activation, leading to relocalization of CTLA-4–containing intracellular vesicles to the immunologic synapse, release of CTLA-4 and up-regulation of CTLA-4 on the cell surface,” Boussiotis wrote. “Under these conditions, anti-CTLA–4 antibodies reverse the inhibitory effect of CTLA-4, which is mediated by B7-1 and B7-2 ligation, and induce long-term antitumor responses.”
These data also indicate CTLA-4 blockade benefit also is dependent upon epitope response, Boussiotis wrote.
“It is tempting to speculate that development of these antitumor responses might also be mediated by memory T cells generated during prior exposure to such antigens that were foreign to the host and happened to be homologous to neo-epitopes induced by somatic mutations in melanomas,” Boussiotis wrote. “Importantly, a high mutational burden increased the likelihood of the development of specific neo-epitopes that would confer clinical benefit from CTLA-4 blockade. In the era of immunotherapy, genetic diversity of cancer may, in fact, be a good thing.”
Disclosure: The study was funded in part by the Frederick Adler Fund. See the study for a list of the researchers’ relevant financial disclosures.
Perspective
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Richard D. Carvajal, MD
The development of ipilimumab (Yervoy, Bristol-Myers Squibb) — an inhibitory antibody targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4) — significantly improves the survival of patients with advanced melanoma. Clinical activity has subsequently been demonstrated with a number of agents modulating other immunological checkpoints, including programmed cell death protein 1 (PD1) and programmed death-ligand 1 (PD-L1). Despite the clinical activity observed with these agents in melanoma, as well as other solid and hematologic malignancies, clinical benefit is not universal. Indeed, only 20% of individuals treated with ipilimumab for advanced melanoma are alive at 3 years. Thus, there is a pressing need for the identification of predictive biomarkers of response that can be utilized to optimally select patients for therapy with CTLA-4 inhibition and other immunological agents.The innovative work conducted by Snyder and colleagues reveals critical information regarding the genetic basis of the melanoma immune response that can be used to identify those most likely to benefit from immunologic checkpoint blockade with ipilimumab and tremelimumab (CP-675,206; Pfizer, MedImmune). The investigators performed whole-exome sequencing of melanoma samples collected from 64 patients treated with CTLA-4 blockade and demonstrated an improved likelihood of response that was associated with a greater burden of genetic mutations within the tumor.
Importantly, some tumors with a high mutation burden did not respond to therapy, demonstrating that tumor burden alone is insufficient to predict response. Using an elegant computational algorithm, they observed that the tumors more responsive to immunotherapy shared a common subset of genetic mutations that encoded for highly immunogenic tumor-specific neoantigens not observed in tumors that did not respond.
Despite the heterogeneity of patient characteristics and the limited sample size, these findings support the selection of patients based upon tumor immunogenicity for CTLA-4 inhibition, as it is in these cases where augmentation of the immune response leads to significant clinical benefit. More broadly, this work highlights the need to reclassify what previously were considered passenger mutations as potentially immunologically relevant genetic events.
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