Giulio Tosti

Phase III comparison of vitespen, an autologous tumor-derived heat shock protein gp96 peptide complex vaccine, with physician's choice of treatment for stage IV melanoma: The C-100-21 study group

PURPOSE To assess the antitumor activity of vitespen (autologous, tumor- derived heat shock protein gp96 peptide complexes) by determining whether patients with stage IV melanoma treated with vitespen experienced longer overall survival than patients treated with physicians choice. PATIENTS AND METHODS Patients (N = 322) were randomly assigned 2:1 to receive vitespen or physicians choice (PC) of a treatment containing one or more of the following: dacarbazine, temozolomide, interleukin-2, or complete tumor resection. This open-label trial was conducted at 71 centers worldwide. Patients were monitored for safety and overall survival. RESULTS Therapy with vitespen is devoid of significant toxicity. Patients randomly assigned to the vitespen arm received variable number of injections (range, 0 to 87; median, 6) in part because of the autologous nature of vitespen therapy. Intention-to-treat analysis showed that overall survival in the vitespen arm is statistically indistinguishable from that in the PC arm. Exploratory landmark analyses show that patients in the M1a and M1b substages receiving a larger number of vitespen immunizations survived longer than those receiving fewer such treatments. Such difference was not detected for substage M1c patients. CONCLUSION These results are consistent with the immunologic mechanism of action of vitespen, indicating delayed onset of clinical activity after exposure to the vaccine. The results suggest patients with M1a and M1b disease who are able to receive 10 or more doses of vitespen as the candidate population for a confirmatory study.

Vitamin D and melanoma and non-melanoma skin cancer risk and prognosis: A comprehensive review and meta-analysis

Vitamin D is formed mainly in the skin upon exposure to sunlight and can as well be taken orally with food or through supplements. While sun exposure is a known risk factor for skin cancer development, vitamin D exerts anti-proliferative and pro-apoptotic effects on melanocytes and keratinocytes in vitro. To clarify the role of vitamin D in skin carcinogenesis, we performed a review of the literature and meta-analysis to evaluate the association of vitamin D serum levels and dietary intake with cutaneous melanoma (CM) and non-melanoma skin cancer (NMSC) risk and melanoma prognostic factors. Twenty papers were included for an overall 1420 CM and 2317 NMSC. The summary relative risks (SRRs) from random effects models for the association of highest versus lowest vitamin D serum levels was 1.46 (95% confidence interval (CI) 0.60-3.53) and 1.64 (95% CI 1.02-2.65) for CM and NMSC, respectively. The SRR for the highest versus lowest quintile of vitamin D intake was 0.86 (95% CI 0.63-1.13) for CM and 1.03 (95% CI 0.95-1.13) for NMSC. Data were suggestive of an inverse association between vitamin D blood levels and CM thickness at diagnosis. Further research is needed to investigate the effect of vitamin D on skin cancer risk in populations with different exposure to sunlight and dietary habits, and to evaluate whether vitamin D supplementation is effective in improving CM survival.

The risk of developing a second primary cancer in melanoma patients: a comprehensive review of the literature and meta-analysis

The number of cutaneous melanoma survivors has been increasing for years due to improvements in early diagnosis and subsequent prolonged survival. These patients are at increased risk of developing a second melanoma and a second primary malignancy (SPM) at other sites as well. We performed a review of scientific literature and meta-analysis to evaluate the risk of developing a SPM (other than melanoma) among melanoma patients. Twenty-three independent papers and over 350,000 melanoma patients were included. Risk of cancer among melanoma survivors was increased overall (1.57, 95% CI 1.29-1.90) and at several sites: bone (2.09, 95% CI 1.08-4.05), non-melanoma skin cancer (4.01, 95% CI 1.81-8.87), soft tissue (6.80, 95% CI 1.29-35.98), colon-rectum (1.12, 95% CI 1.00-1.25), female breast (1.14, 95% CI 1.07-1.22), kidney (1.34, 95% CI 1.23-1.45), prostate (1.25, 95% CI 1.13-1.37) and non-Hodgkin lymphoma (1.37, 95% CI 1.22-1.54). The overall risk of SPM showed a tendency to decrease as the time from melanoma diagnosis lengthened. Most of our findings may be explained by the tendency of some exposures, which are risk factors for different tumors, to occur simultaneously in the same individuals. These results suggest primary and secondary cancer prevention counselling for melanoma survivors.

Utility of electrochemotherapy in melanoma treatment.

Purpose of review In the present study, the role of electrochemotherapy (ECT) in the advanced melanoma setting, either as alternative treatment modality to conventional therapies or as palliative care, is reviewed and the perspective to combine ECT with biological response modifiers and immunotherapeutic compounds is discussed. Recent findings ECT refers to the combination of electroporation and administration of anticancer drugs for local treatment of solid neoplasms. Electroporation uses short and intense electric pulses to induce a transient permeabilization of the cell membrane by creation of pores, thus allowing molecules, such as chemotherapeutic agents, to freely diffuse into the cytosol. ECT has shown to be effective and clinically well tolerated in the local control of primary and metastatic solid tumors of diverse histotypes in preclinical and clinical studies, thus, emerging as useful local treatment modality for disseminated superficial melanoma. So far, only a few data on the role of immunological response in ECT-treated patients have been reported. Summary Treatment regimens combining ECT to biological response modifiers (interleukin-2, interferon) and immunotherapeutic compounds should be further explored in animal and human cancer models; immunotherapy combined to ECT could broaden the therapeutic indications of ECT, by rendering it effective also on distant unreachable or untreated lesions.

In Vivo Genetic Screens of Patient-Derived Tumors Revealed Unexpected Frailty of the Transformed Phenotype

UNLABELLED The identification of genes maintaining cancer growth is critical to our understanding of tumorigenesis. We report the first in vivo genetic screen of patient-derived tumors, using metastatic melanomas and targeting 236 chromatin genes by expression of specific shRNA libraries. Our screens revealed unprecedented numerosity of genes indispensable for tumor growth (∼50% of tested genes) and unexpected functional heterogeneity among patients (<15% in common). Notably, these genes were not activated by somatic mutations in the same patients and are therefore distinguished from mutated cancer driver genes. We analyzed underlying molecular mechanisms of one of the identified genes, the Histone-lysine N-methyltransferase KMT2D, and showed that it promotes tumorigenesis by dysregulating a subset of transcriptional enhancers and target genes involved in cell migration. The assembly of enhancer genomic patterns by activated KMT2D was highly patient-specific, regardless of the identity of transcriptional targets, suggesting that KMT2D might be activated by distinct upstream signaling pathways. SIGNIFICANCE Drug targeting of biologically relevant cancer-associated mutations is considered a critical strategy to control cancer growth. Our functional in vivo genetic screens of patient-derived tumors showed unprecedented numerosity and interpatient heterogeneity of genes that are essential for tumor growth, but not mutated, suggesting that multiple, patient-specific signaling pathways are activated in tumors. Cancer Discov; 6(6); 650-63. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 561.

Heat-shock proteins-based immunotherapy for advanced melanoma in the era of target therapies and immunomodulating agents.

Introduction: Heat-shock proteins (HSPs) are highly conserved, stress-induced proteins that function as chaperones, stabilizing proteins and delivering peptides. Tumor-derived HSP peptide complexes (HSPPCs) induced immunity against several malignancies in preclinical models, exhibiting activity across tumor types. Areas covered: HSPPC-based vaccination showed clinical activity in subsets of patients with different malignancies (e.g., gastric, colorectal, pancreatic, ovarian cancer, and glioblastoma). In Phase III clinical trials for advanced melanoma and renal cell carcinoma patients, HSPPC-based vaccine demonstrated an excellent safety profile, thus emerging as a flexible tumor- and patient-specific therapeutic approach. Expert opinion: Melanoma, renal clear cell carcinoma, and glioblastoma are among suitable targets for HSP-based treatment as demonstrated by immune responses and clinical activity observed in subsets of patients, mainly those with early stage of disease and limited tumor burden. In order to further improve clinical activity, combinations of HSPPC-based vaccines with mutation-driven therapies, antiangiogenic agents, or immunomodulating monoclonal antibodies should be tested in controlled clinical trials.

Anti-cytotoxic T lymphocyte antigen-4 antibodies in melanoma.

Approaches aimed at enhancement of the tumor specific response have provided proof for the rationale of immunotherapy in cancer, both in animal models and in humans. Ipilimumab, an anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) antibody, is a new generation immunotherapeutic agent that has shown activity in terms of disease free and overall survival in metastatic melanoma patients. Its use was approved by the US Food and Drug Administration in March 2011 to treat patients with late stage melanoma that has spread or that cannot be removed by surgery. The mechanism of action of CTLA-4 antibodies in the activation of an antitumor immune response and selected clinical studies of ipilimumab in advanced melanoma patients are discussed. Ipilimumab treatment has been associated with immune related adverse events due to T-cell activation and proliferation. Most of these serious adverse effects are associated with the gastrointestinal tract and include severe diarrhea and colitis. The relationship between immune related adverse events and antitumor activity associated with ipilimumab was explored in clinical studies. Potential biomarkers predictive for clinical response and survival in patients treated with anti-CTLA-4 therapy are presently under investigation. Besides the conventional patterns of response and stable disease as defined by standard Response Evaluation Criteria in Solid Tumors criteria, in subsets of patients, ipilimumab has shown patterns of delayed clinical activity which were associated with an improved overall survival. For this reason a new set of response criteria for tumor immunotherapy has been proposed, which was termed immune related response criteria. These new criteria are presently used to better analyze clinical activity of immunotherapeutic regimens. Ipilimumab is currently under investigation in combination with other treatments, such as chemotherapy, target agents, radiotherapy, and other immuno-therapeutic regimens.

Sarcoma spreads primarily through the vascular system: Are there biomarkers associated with vascular spread?

Sarcomas are a heterogeneous group of tumors with specific molecular characteristics and currently classified on the basis of their tissue of origin and histologic appearance. Except for epithelioid sarcoma, clear cell sarcoma, angiosarcoma and rhabdomyosarcoma, which may spread to regional lymph nodes, the other histotypes spread via the vascular system to the lungs most of the time. A variety of molecular approaches, including gene expression profiling, have identified candidate biomarkers and generated insights into sarcoma biology. The comprehension of the pathogenesis of this malignancy according to the mesenchymal stem cell hypothesis parallels the description of several molecular pathways deregulated in sarcoma. Individuation of vascular spread biomarkers is actually focused on the study of factors involved both in hemostasis and angiogenesis. Interestingly the microenvironment of sarcomas showed the very same mesenchymal origin of the surrounding stromal cells. The presence of circulating tumor cells and miRNAs in blood samples of sarcoma patients represents the possibility not only to better stratify patients group according to the prognosis but also to tailor new individualized therapy. So, it could be predicted that some genes expressed in a specific sarcoma might have prognostic significance or therapeutic targeting potential and molecular targets can be identified in the tumor or in the tumor microenvironment. Therefore the initial evaluation of a sarcoma patient should include in-depth genetic evaluation including karyotyping and c-DNA/protein expression profiling. The chemokine signaling demonstrated to be deeply implicated in sarcoma development as well as to have a significant role in development of metastatic disease, especially in directing tumor cells towards the preferential sites of metastases in sarcoma, lung and bone. It is unsolved if the blood stream is a more favorable environment compared to lymphatic or if lymph nodes are more efficient in destroying metastatic sarcoma cells. But the comprehension of the regulatory mechanisms of the behavior of mesenchymal malignant tumors is at its dawn.

Sunny Holidays before and after Melanoma Diagnosis Are Respectively Associated with Lower Breslow Thickness and Lower Relapse Rates in Italy

Background Previous studies have reported an association between sun exposure and improved cutaneous melanoma (CM) survival. We analysed the association of UV exposure with prognostic factors and outcome in a large melanoma cohort. Methods A questionnaire was given to 289 (42%) CM patients at diagnosis (Group 1) and to 402 CM patients (58%) during follow-up (Group 2). Analyses were carried out to investigate the associations between sun exposure and melanoma prognostic factors and survival. Results Holidays in the sun two years before CM diagnosis were significantly associated with lower Breslow thickness (p=0.003), after multiple adjustment. Number of weeks of sunny holidays was also significantly and inversely associated with thickness in a dose-dependent manner (p=0.007). However when stratifying by gender this association was found only among women (p=0.0004) the risk of CM recurrence in both sexes was significantly lower in patients (n=271) who had holidays in the sun after diagnosis, after multiple adjustment including education: HR=0.30 (95%CI:0.10-0.87; p=0.03) conclusions: Holidays in the sun were associated with thinner melanomas in women and reduced rates of relapse in both sexes. However, these results do not prove a direct causal effect of sun exposure on survival since other confounding factors, such as vitamin D serum levels and socio-economic status, may play a role. Other factors in sun seeking individuals may also possibly affect these results.

Heat shock protein peptide complex 96-based vaccines in melanoma How far we are, how far we can get

Heat shock proteins (HSPs) are highly conserved, stress-induced proteins that function as chaperones stabilizing and delivering peptides. In several preclinical studies, tumor derived HSP-peptide complexes (HSPPCs) have been shown to induce immunity against several malignancies. HSP-based vaccines, indeed, work across tumor types, bypassing the need for the identification of the single immunogenic peptide and thus emerging as a class of tumor- and patient-specific vaccines. HSPPC-96-based vaccine vitespen® (formerly Oncophage®) is the first autologous cancer vaccine made from individual patients’ tumors which not only confirmed its activity in different malignancies (e.g., gastric cancer, colorectal cancer, pancreatic cancer, non-Hodgkin’s lymphoma and chronic myelogenous leukemia), but was also successfully tested in phase III clinical trials in melanoma and kidney cancer. HSPPC-96-based vaccine also demonstrated an excellent safety profile with almost no toxicity. HSP-based vaccines are emerging as a novel therapeutic approach with a suggestive role in cancer therapy.