Gary schwartz dna doctor8/28/2023 ![]() Many different vaccination approaches have been attempted in melanoma, including whole-cell vaccines, peptide/protein-based vaccines, ganglioside vaccines, dendritic-cell based therapy, recombinant viral vectors and DNA vaccines. In another disease setting, castrate-resistant prostate cancer, the approval of Sipuleucel-T, a dendritic cell vaccine, demonstrated that tumor vaccination strategies have the potential to provide clinical benefit for advanced cancer patients. These efforts culminated in the milestone approval of ipilimumab, a monoclonal antibody against cytotoxic T-lymphocyte antigen-4 (CTLA-4), in March 2011 for patients with refractory melanoma. Strategies to harness the immune system against melanoma have included cytokine therapy, immune-modulating antibodies, adoptive T-cell therapy, and vaccines. Melanoma is an attractive target for immunotherapy because of its selective expression of differentiation antigens not expressed by other tissues. Consequently, there is a strong interest in developing more effective and better tolerated adjuvant therapies. The only Food and Drug Administration (FDA)-approved adjuvant therapy for melanoma is high-dose interferon-α (IFN-α), which consistently improves relapse-free survival, but not overall survival, and is associated with significant toxicities. While most early stage malignant melanomas can be cured by surgical excision alone, the relapse rates of high-risk melanomas (Breslow thickness >4 mm or loco-regional metastases) remain high after surgery. ConclusionsĪ regimen of five immunizations with pINGmuTyr administered by EP was found to be safe and resulted in Tyr-reactive immune responses in six of 15 patients at 1.5 mg dose cohort. After a median follow-up of 40.9 months, median survival has not been reached. One patient subsequently received ipilimumab and developed an enhanced Tyr-reactive response with polyfunctional cytokine profile. Epitope spreading of CD8 + T cell response to NY-ESO-1 was observed in one patient with vitiligo. No Tyr-reactive CD8 + T cell response was detected in the 0.2 mg and 0.5 mg dose cohort patients. Six of 15 patients (40%) in the 1.5 mg dose cohort developed Tyr-reactive CD8 + T cell responses following stimulation, defined as a ≥3 standard deviation increase in baseline reactivity by tetramer or ICS assays. The only common toxicity was grade 1 injection site reaction. Twenty-four patients received ≥1 dose of the pINGmuTyr vaccine PBMCs from 21 patients who completed all five doses were available for Tyr immune assays. Peripheral blood mononuclear cells (PBMC) were collected, cultured with a peptide pool containing eight HLA class I-restricted Tyr-specific T-cell epitopes, and analyzed by HLA-A*0101-restricted tetramers and intracellular cytokine staining (ICS). Human leukocyte antigen (HLA)-A1, A2, A24 or B35 stage IIb-IV melanoma patients received up to five doses of the mouse tyrosinase DNA vaccine by EP every three weeks at dose levels of 0.2 mg, 0.5 mg, or 1.5 mg per injection. To further define the optimal vaccination strategy, we conducted a phase I study of in vivo electroporation (EP) of a murine Tyr DNA vaccine (pINGmuTyr) in malignant melanoma patients. Prior studies show that intramuscular injection and particle-mediated epidermal delivery of xenogeneic melanosomal antigens (tyrosinase or Tyr, gp100) induce CD8 + T cell responses to the syngeneic protein.
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