Biomedical subjects

Johanne M Kaplan

Publications and source records attributed to Johanne M Kaplan.

6 recordsLinked to original sources

PubMed2005

Adenovirus-based cancer gene therapy.

Over the past decade, adenovirus (Ad)-based vectors have been used extensively in the context of cancer gene therapy. Two basic strategies have been pursued for the use of Ad vectors in cancer gene therapy: 1) approaches aimed at direct tumor cell killing through delivery of replicating oncolytic viruses or non-replicating vectors encoding tumor suppressor genes, suicide genes or anti-angiogenic genes, and 2) immunotherapeutic approaches aimed at inducing host anti-tumor immune responses that can destroy tumor cells at both primary and metastatic locations. Both strategies offer the potential of selective tumor cell destruction without damage to normal tissues. Extensive pre-clinical and clinical studies have been conducted based on these strategies. Encouraging results have been obtained but robust clinical efficacy remains elusive. Several obstacles limiting the therapeutic activity of Ad vectors have been encountered, including efficiency of tumor cell transduction and inhibition of efficacy by anti-Ad host immune responses. However, expanding knowledge in the areas of Ad biology and tumor biology continues to lead to increasingly sophisticated approaches to address these issues. A review of various Ad-based cancer gene therapy approaches and recent progress in the area are presented herein.

Adenoviruses, Human↗

PubMed2004

New cancer vaccine approaches.

The use of tumor vaccines as a therapeutic modality for the treatment of cancer is a very exciting and promising area of research. Unlike chemotherapy, vaccination against tumor antigens has the potential to specifically target cancer cells without damage to normal tissues or debilitating side effects. Recent progress in immunology and tumor biology has allowed for the development of new vaccination strategies and approaches to enhance clinical efficacy.

Antigens, Neoplasm↗

PubMed2003

Induction of specific antitumor immunity in the mouse with the electrofusion product of tumor cells and dendritic cells.

Dendritic cells (DCs) are potent antigen-presenting cells capable of inducing primary T-cell responses. Several immunotherapy treatment strategies involve manipulation of DCs, both in vivo and ex vivo, to promote the immunogenic presentation of tumor-associated antigens. In this study, an electrofusion protocol was developed to induce fusion between tumor cells and allogeneic bone marrow-derived DCs. Preimmunization with irradiated electrofusion product was found to provide partial to complete protection from tumor challenge in the murine Renca renal cell carcinoma model and the B16 and M3 melanoma models. Vaccinated survivors developed specific immunological memory and were able to reject a subsequent rechallenge with the same tumor cells but not a syngeneic unrelated tumor line. Antitumor protection in the B16 model was accompanied by the development of a polyclonal cytotoxic T-lymphocyte response against defined melanoma-associated antigens. The therapeutic potential of this type of approach was suggested by the ability of a Renca-DC electrofusion product to induce tumor rejection in a substantial percentage of hosts (60%) bearing pre-established tumor cells. These results indicate that treatment with electrofused tumor cells and allogeneic DCs is capable of inducing a potent antitumor response and could conceivably be applied to a wide range of cancer indications for which tumor-associated antigens have not been identified.

Animals↗

PubMed2002

Solid-phase epitope recovery: a high throughput method for antigen identification and epitope optimization.

Self tolerance to MHC class I-restricted nonmutated self Ags is a significant hurdle to effective cancer immunotherapy. Compelling evidence is emerging that altered peptide ligands can be far more immunogenic than their corresponding native epitopes; however, there is no way to reliably predict which modifications will lead to enhanced native epitope-specific immune responses. We reasoned that this limitation could be overcome by devising an empirical screen in which the nearly complete combinatorial spectrum of peptides of optimal length can be rapidly assayed for reactivity with a MHC class I-restricted cytotoxic T cell clone. This method, solid-phase epitope recovery, quantitatively ranks all reactive peptides in the library and allows selection of altered peptide ligands having desirable immunogenic properties of interest. In contrast to rationally designed MHC anchor-modified peptides, peptides identified by the present method are highly substituted in predicted TCR contact residues and can reliably activate and expand effector cell populations in vitro which lyse target cells presenting the wild-type epitope. We demonstrate that solid-phase epitope recovery peptides corresponding to a poorly immunogenic epitope of the melanoma Ag, gp100, can reliably induce wild-type peptide-specific CTL using normal donor T cells in vitro. Furthermore, these peptides can complement one another to induce these responses in an overwhelming majority of normal individuals in vitro. These data provide a rationale for the design of superior vaccines comprising a mixture of structurally diverse yet functionally convergent peptides.

Antigen Presentation↗

PubMed2002

Tumor treatment with complexes of cationic lipid and noncoding plasmid DNA results in the induction of cytotoxic T cells and systemic tumor elimination.

We have demonstrated recently that treatment of established peritoneal mesothelial tumors with complexes composed of cationic lipid and noncoding plasmid DNA (pNull) results in the inhibition of tumor growth accompanied by the induction of a tumor-specific cellular immune response. In this study, treatment of mice bearing intraperitoneal (i.p.) M3 melanoma tumors with i.p. injections of lipid/pNull complex was found to inhibit tumor growth and induce the development of a cytolytic response against several M3 melanoma-associated antigens. Depletion of CD8(+) T cells, as opposed to natural killer (NK) or CD4(+) T cells, essentially abrogated the therapeutic effect of lipid+pNull complex, thus supporting the involvement of cytotoxic CD8(+) T cells in the antitumor response. The antitumor effect of lipid/pNull complex was maximal following delivery into a tumor-bearing compartment. For example, i.p. delivery of complex was more effective than intravenous (i.v.) or subcutaneous (s.c.) treatment of i.p. M3 tumors. In addition, i.v. injection of complex displayed therapeutic activity against lung metastases caused by i.v. injection of tumor cells, and intratumoral injection of complex into solid s.c. tumors caused regression in most animals. Importantly, the immune response induced by local treatment of tumors with complex also offered systemic protection against tumor cells at distal sites, as illustrated by the eradication of both peritoneal tumors and lung metastases in mice treated with complex delivered i.p. Treatment with lipid/pNull complex, therefore, represents an attractive immune-based treatment modality that could potentially be applied to many tumor types.

Animals↗

PubMedDate not supplied

Enhanced efficacy of melanoma vaccines in the absence of B lymphocytes.

Provoking a specific cellular immune response against tumor-associated antigens is a promising therapeutic strategy to treat cancers with defined antigens such as melanoma. In recent clinical trials, however, immune responses against melanoma antigens have been elicited without consistent clinical responses, suggesting the need for approaches that potentiate the specific cellular immune response. Since B lymphocytes have been reported to exert a negative effect on the cellular arm of the immune response in certain model systems, the authors compared the protective immunity elicited by melanoma antigens in B cell-deficient microMT mice to that obtained in fully immunocompetent C57BL/6 mice. Immunization with melanoma-associated antigens was accomplished using recombinant adenovirus (Ad) vectors encoding human gp100 (Ad2/gp100) or murine TRP-2 (Ad2/mTRP-2). A single dose of Ad2/gp100 or Ad2/mTRP-2 inhibited the growth of established subcutaneous B16 melanoma tumors in B cell-deficient but not wild-type C57BL/6 mice. The enhanced tumor protection observed in B cell-deficient mice appeared to be associated with potentiation of the magnitude and longevity of the specific cellular immune response. Natural killer (NK) cells were also found to be essential to the protective immune response in microMT mice because NK cell depletion with anti-asialo-GM1 antibody resulted in both the loss of tumor growth suppression and attenuation of the specific cellular immune response. The authors conclude that the protective cell-mediated immunity provoked by Ad-based cancer vaccines is enhanced in the absence of B cells, suggesting that a therapeutic regimen that includes depletion of B lymphocytes may be beneficial to cancer vaccine therapy.

Adenoviridae↗