Immunization with a tumor-cell-lysate-loaded autologous-antigen-presenting-cell-based vaccine in melanoma

Abstract

The discoveries of human melanoma-associated antigens in molecular terms have renewed interest in peptide- or peptide- and antigen-presenting-cell (APC)-based cancer vaccines. Considering the limited scope of immunization using defined peptides, we have studied an alternative approach of specific immunization with tumor-lysate-loaded autologous APC (adherent peripheral mononuclear cells cultured in 1000 U granulocyte/macrophage-colony-stimulating factor for 14 days) as a surrogate vaccine. Seventeen patients (11 with active metastatic disease) were intradermally immunized with the vaccine in a phased dose escalation (10(5)-10(7) cells/injection) monthly for 4 months. Thirteen patients completed all four immunizations showing no toxicity (3 patients had to be taken off study because of progressive disease and 1 patient went off study as a result of myocardial infarction due to multi-vessel coronary artery disease). None has shown any immediate or delayed toxicity attributable to the immunization and none has shown any evidence of autoimmunity. One patient showed a partial regression of a subcutaneous nodule. Thirteen patients are alive after 4+ months to 30+ months (17-month median survival for the group). Nine patients showed evidence of delayed-type hypersensitivity at the vaccine sites. Monitoring of biological response in conventional natural killer or cytolytic T lymphocyte assays with pre- and post-immune peripheral blood lymphocytes revealed no consistent differences. The vaccine-infiltrating lymphocytes (VIL) from nine specimens were adequately expanded following in vitro stimulation with the respective autologous-lysate-loaded APC for phenotypic and functional analyses. Five of the nine ex vivo expanded VIL were predominantly CD8+. Evidence of an antigen-specific CD8+ T cell response (cytotoxicity and/or tumor necrosis factor production) was detected in three of the five CD8+ VIL. These observations suggest that this type of vaccine is feasible, that it has biological activity, and that the approach may be improved through additional strategic manipulations.

Tumor Regression Induced by Intratumor Therapy with a Disabled Infectious Single Cycle (DISC) Herpes Simplex Virus (HSV) Vector, DISC/HSV/Murine Granulocyte-Macrophage Colony-Stimulating Factor, Correlates with Antigen-Specific Adaptive Immunity

“…A variety of strategies to develop therapeutic cancer vaccines have been adopted, including immunization with peptides, recombinant proteins, DC pulsed with peptides or tumor cell lysates, and tumor cells transduced with recombinant viruses or plasmid DNAs encoding immune response genes (18,19). Several viruses, including retroviruses, adenoviruses, adeno-associated virus, vaccinia, and HSV, have been genetically modified to express cytokines and costimulatory molecules and used as vectors in cancer therapy (13, 20 -22).…”

Dendritic Cell-Based Immunotherapy of Breast Cancer: Modulation by CpG

“…In Phase I, 5 groups of patients with measurable MBC will receive 2 sets of intradermal (i.d.) vaccinations given 7 days apart consisting of at least 10^ tumor-loaded DCs admixed with an escalating dose (16,32,48, 64 and 80 mg) of CpG 7909. This dosing range of CpG 7909 has been previously tested in patients with cancer and found to be safe, with no grade III/IV toxicities (NCI Common Toxicity Criteria, v.3, http:// www.fda.gov/cder/cancer/ toxicityframe.htm) (A. Krieg, Coley Pharmaceuticals, personal communication).…”

Generation of cellular immune responses to antigenic tumor peptides

“…One patient had a partial response of the tumor, and 9 had a delayed type hypersensitivity (DTH) response; no CTLs were evident, but after expanding T cells in vitro with autologous loaded APCs, CD8 + CTLs were found in 5/9 [109]. In other studies DCs generated with GM-CSF and IL-4 were pulsed with a tumor lysate or a mixture of peptides and injected into patients together with KLH [110]. Sixteen patients with advanced melanoma were immunized; all developed a DTH response to keyhole limpet hemocyanin (KLH) and 11/16 to the melanoma peptides; tumor responses were found in 5/16 patients with regression of metastases in organs of the skin, lung and pancreas (two complete responses, three partial responses) [110].…”