Pierre Coulie, MD, PhD (de Duve Institute and Université Catholique de Louvain) and Victor H. Engelhard, PhD (University of Virginia School of Medicine) co-chaired a session on vaccine combinations. Dr. Coulie addressed the numbers and functions of lymphocytes in human melanoma metastases. Vaccine trials in metastatic melanoma have used a variety of tumor-specific Ag administered as peptides, proteins, peptide-pulsed DCs, and recombinant poxviruses. Among patients who displayed tumor regression (10% - 20%), the number of anti-vaccine CTLs was low. Further analysis indicated that tumor regression was linked with activation of CTLs that recognize other tumor-specific antigens not included in the vaccine, and that some of these CTLs were in the blood and tumors prior to vaccination. New CTLs appeared following vaccination. These included both new clones against antigens targeted prior to vaccine administration (i.e., clonal spreading) and new clones against previously ignored antigens (i.e., antigen spreading). Dr. Coulie suggested that melanoma patients spontaneously mount anti-tumor CTL responses that become inefficient at rejecting the tumor due to local immunosuppression or reduced tumor antigen expression. Vaccination may activate a small number of anti-vaccine CTLs, which upon trafficking to the tumor, may relieve suppression and promote activation of many other anti-tumor CTLs that contribute to tumor regression.
Victor H. Engelhard, PhD (University of Virginia School of Medicine) discussed immunological proteomics, the identification of phosphorylated peptide antigens displayed on cancer cells, and prospects for their use as immunotherapeutics. Dr. Engelhard noted that few of the currently identified melanoma Ags are from proteins associated with transformation and/or metastasis. Identification of Ags from proteins associated with control of cell growth, survival or metastasis may be useful because alteration of these essential proteins associated with immune evasion may comprise survival of the tumor cell.
Phosphorylation of signaling molecules regulates activation and proliferation of many cancers. Dr. Engelhard and colleagues have developed a strategy to identify MHC-associated peptides modified by intracellular phosphorylation using mass spectrometry. This has allowed isolation of a small number of peptides that are associated with cellular transformation or metastasis. As a candidate for immunotherapy, the phosphopeptide should be expressed on melanomas from multiple patients, with little or no expression on normal cells. It should be associated with an aspect of malignancy and must be immunogenic. Ideally, it would be expressed on other kinds of cancer cells as well. Phosphopeptides associated with melanoma are immunogenic. Phosphopeptide-specific CD8 T cells differentiate between the phosphorylated and non-phosphorylated peptides and recognize melanoma cells. Dr. Engelhard and colleagues have recently demonstrated that the phosphate moiety is readily accessible for direct interaction with the TCR and the MHC molecule, increasing the peptides affinity and modifying its conformation. Thus, phosphorylation can generate new Ags. MHC-restricted phosphopeptides warrant further investigation as potential targets for melanoma immunotherapy.
Hideho Okada, MD, PhD (University of Pittsburgh Cancer Institute) presented on the induction of CD8+ T cell responses against novel glioma-associated antigen (GAAs) peptides and clinical activity by vaccinations with αDC1s and Poly-ICLC in patients with recurrent malignant glioma. The first four vaccines induced positive immune responses against at least one of the targeted GAAs in 11 of 19 patients, with booster vaccination leading to positive responses in an additional four patients. Type 1 cytokines and chemokines were up-regulated and eight patients experienced progression free status ≥12 months; one patient with recurrent glioblastoma multiforme achieved sustained clinical response. IL-12 production by αDC1s correlated positively with PFS.
Jedd D. Wolchok, MD, PhD (Memorial Sloan-Kettering Cancer Center) discussed endogenous and exogenous vaccination in the context of immunologic checkpoint blockade. Dr. Wolchok reviewed data that demonstrate that CTLA-4 blockade with ipilimumab results in prolonged survival of patients with refractory melanoma. Moreover, clinical response has been associated with changes in absolute lymphocyte count, NY-ESO-1 immunity, and induction of ICOS expression on CD4+ T cells. These responses require prospective evaluation in ongoing clinical trials. Indeed, the tumor microenvironment remains fertile ground to study the mechanism underlying immunologic checkpoint blockade.
Saskia J. Santegoets, PhD (VU University Medical Center) presented on T cell activation, PSMA seroconversion and increased Th17 rates associated with favorable clinical outcome in prostate cancer patients treated with prostate GVAX and anti-CTLA-4 immunotherapy. Dr. Santegoets reported that treatment was associated with induction of T cell activation and that rates of Tregs increased in patients with progressive disease (PD), but not in those with partial response (PR) or stable disease (SD). Indeed, elevations in Treg levels were associated with reduced survival. Treatment with GVAX/ipilimumab led to Th17/Th2 polarization, with Th17 induction coinciding with the onset of immune-related adverse events and a decline in PSA, and induction of Th2 associated with better OS. Dr. Santegoets reported serological PSMA responses associated with treatment and that PSMA seroconversion was associated with improved OS.
Willem W. Overwijk, PhD (University of Texas, MD Anderson Cancer Center) presented data suggesting that vaccine sites can serve as sinks and become a "graveyard" for tumor-specific T cells. Dr. Overwijk's results indicate that oil-based, long-lived vaccine formulations activate T cells, but eventually tolerize the cells. While this tolerance can be overcome with additional adjuvants, oil-based vaccines tend to sequester T cells at the vaccine site and limit T cell accumulation in the tumor. Thus, long-lived vaccines can induce sub-optimal anti-tumor immunity. Water-based, short-lived vaccine formulations require additional adjuvants to activate T cells, but do not tend to sequester T cells at the vaccine site. Consequently, these formulations allow T cell accumulation in the tumor and may have greater therapeutic efficacy than long-lived formulations. Thus short-lived vaccine formulations warrant further evaluation.
Antoni Ribas, MD (University of California, Los Angeles) presented final efficacy results of A3671009, a phase III study of tremelimumab versus chemotherapy (dacarbazine or temozolomide) in first-line patients with unresectable melanoma. Compared with chemotherapy, tremelimumab resulted in a nonsignificant improvement in survival. The duration of first objective tumor responses to tremelimumab was significantly longer than responses to chemotherapy. A low baseline level of C reactive protein (CRP) and a baseline absolute lymphocyte count in the normal range selected for patients with higher tumor response rate and better survival outcome with tremelimumab compared with chemotherapy, which may reflect an interaction between the tumor microenvironment, tumor inflammation, and an adaptive immune response.