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Mike Whelan

Publications and source records attributed to Mike Whelan.

7 recordsLinked to original sources
PubMed2006

Biomarkers for the development of cancer vaccines: current status.

Significant improvements in our knowledge of tumor immunology have resulted in more sophisticated vaccine approaches for the treatment of cancer. However, research into biomarkers that correlate with the clinical outcome of immunotherapy has lagged behind vaccine development. To this extent, very few immunological or other markers exist that can be used in clinical trials for immunotherapy. In this review, we discuss the current status of biomarker development specifically for the monitoring and development of cancer vaccines. This includes immunological biomarkers (measurement of T-cell and cytokine responses), autoimmunity as a correlate for treatment outcome, and the possible development of multiple biomarkers using high-throughput proteomics technologies. The generation of such biomarkers will allow us to make clinical decisions about patient treatment at an earlier stage and should aid in shortening the development time for vaccines.

Animals↗
PubMed2005

The biological effects of syngeneic and allogeneic cytokine-expressing prophylactic whole cell vaccines and the influence of irradiation in a murine melanoma model.

Allogeneic whole tumour cell vaccines are inherently practical compared with autologous vaccines. Cell lines are derived from allogeneic tumour, grown in bulk and then administered as a vaccine to the patient, following irradiation, which not only prevents any replication but also enhances antigen presentation. Protection is believed to occur through the presentation of antigens shared between the syngeneic and allogeneic tumours. Although cytokine-transfected tumour whole cell vaccines have been used clinically, little data is available comparing the effects of immunomodulatory cytokine-transfection directly on the same cells when used as both an allogeneic and autologous vaccine. To address this, weakly immunogenic B16-F10 (H-2b) murine melanoma was transfected to secrete either GM-CSF, IL-4 or IL-7. Prophylactic vaccination of both syngeneic C57/BL6 (H-2b) (B6) and allogeneic C3H/Hej (H-2k) (C3H) mice showed the effects of transfected cytokine varied between models. Both GM-CSF and IL-7 significantly (P<0.05) increased the levels of protection within syngeneic B6 mice, but had a diminished effect (P>0.05) within C3H allogeneic mice. Allogeneic B16-F10 cells and syngeneic K1735 cells generated CTL against K1735 suggesting cross-reactive immunity. Using cells labeled with fluorescent dye we demonstrate that irradiated vaccines, of either syngeneic or allogeneic origin, appear to generate potent immune responses and fragments of either vaccine remain at the injection site for up to 9 days. This study shows that protection can be enhanced in vivo by using transfected cytokine, but suggests that irradiated whole cell vaccines, of either tissue-type, are rapidly processed. This leads to the conclusion that the cytokine effects are transient and thus transfection with cytokine may be of limited long-term use in situ.

Animals↗
PubMed2005

Novel immunotherapeutic approaches to prostate cancer.

Immunotherapy offers new and exciting therapeutic options for patients with late-stage prostate cancer. While the concept of using the immune system to combat cancer is not new, it is only in this post-genomics era that the realistic possibility exists of effectively harnessing the immune system against disease. Immunotherapies can be loosely divided into three major categories: non-specific immune stimulation, specific target antigens and whole-cell approaches. All three systems have merits and drawbacks, although the goal of overcoming 'self' tolerance is common to all of them. This review highlights some of the more recent experiments in each of these three fields, focusing particularly on prostate cancer. We suggest that it is unlikely that one single cancer antigen exists and that recent data support this by showing that strong immune responses to prostate antigens can be elicited in a variety of ways. Therefore, a multivalent approach is likely to be most clinically efficacious. Data gathered from the past three years are discussed in this review and lead to the inescapable conclusion that immunotherapy is now a reality.

Antigens↗
PubMed2004

Dendritic cell immunotherapy for urological cancers using cryopreserved allogeneic tumour lysate-pulsed cells: a phase I/II study.

OBJECTIVE: To assess the feasibility, toxicity and immunogenicity of dendritic cell (DC)-based immunotherapy in patients with advanced urological cancers. PATIENTS AND METHODS: Patients with hormone-refractory prostate cancer (11) and metastatic renal cell carcinoma (five) received 1-3 x 10(6) intradermal allogeneic tumour lystate-pulsed DCs fortnightly for six vaccinations then monthly until disease progression. Intradermal keyhole limpet haemocyanin was injected near the DCs as the adjuvant. DC vaccine was prepared from buffy coats, then lysate-pulsed, cryopreserved in aliquots, and tested for phenotypic expression and activity in an allogeneic mixed lymphocyte reaction before clinical use. RESULTS: There was no evidence of significant toxicity from vaccine or adjuvant. Delayed-type hypersensitivity skin testing and biopsy revealed a cellular infiltrate to intradermal re-challenge to tumour lysate and adjuvant in almost all patients. In addition, there was increased expression of T helper type 1 cytokines, interferon-gamma-expressing T cell by ELISPOT analysis, but also interleukin-10 in a few patients. Vaccination resulted in a reduction in the level of prostate-specific antigen (PSA) in one patient, a reduction in PSA velocity in a further man and an increased PSA doubling time in six. Two of five patients with renal cell carcinoma had stabilization of disease. CONCLUSION: The cryopreservation and repeated administration of DC vaccine was feasible and not toxic. There was evidence of induction of both humoral and cellular immunity to vaccine and adjuvant in most patients. The use of sequential aliquots of identical cryopreserved vaccine will ensure quality control and greatly facilitate future clinical studies in terms of consistency of vaccine administered and the provision of primed DCs for in vitro assessment of response.

Adjuvants, Immunologic↗
PubMed2004

Allogeneic tumor-dendritic cell fusion vaccines for generation of broad prostate cancer T-cell responses.

Antigen-loaded dendritic cells (DC) are considered potent stimulators of protective immunity. In some studies, DC hybridized with tumor cells have shown promising antitumor responses in mice as well as in humans. A practical drawback of this approach is the limited availability of autologous tumor samples. We investigated the possibility of hybridizing allogeneic prostate cancer cells with human-monocyte-derived DC, and thereby combine the wide repertoire of antigens from the tumor cells with the costimulatory features of the autologous antigen-presenting cells. Three tumor cell lines were used for hybridization using polyethylene glycol (PEG). We show that all three cell lines formed hybrids with DC to the same extent and without significant loss of viability. Restimulation of autologous T cells with these hybrids resulted in generation of tumor-specific IFNgamma-producing T cells with all three tumor cell lines. Similar tumor specificity could not be obtained if T cells were stimulated using a mixture of non-PEG-fused tumor cells and DC. Moreover, these T cells were capable of specific recognition of other tumor cells of prostate cancer origin and autologous DC pulsed with lysate from these prostate cancer cell lines, while a panel of unrelated EBV-transformed B cell lines were not recognized. These results are strongly indicative of the true tumor specificity of these T cells. Our results suggest that DC hybridized with allogeneic prostate cancer cell lines are potent stimulators of a broad prostate-tumor-specific response.

Antigens, Neoplasm↗
PubMed2003

Cancer immunotherapy: an embarrassment of riches?

There is clear evidence that certain forms of immunotherapy can be successful against certain cancers. However, it would appear that cancerous cells of various origin are exceptionally adept at subverting the immune response. Consequently, it is probable that the most efficacious therapy will be one in which multiple responses of the immune system are activated. There is currently an embarrassment of riches with regard to multiple vaccine strategies in the clinic, although no single method seems to hold the solution. Here, we draw together several of the humoral- and cellular-activating strategies currently under clinical investigation.

Antigens, Neoplasm↗