Steven D. Bines

OPTIM trial: a Phase III trial of an oncolytic herpes virus encoding GM-CSF for unresectable stage III or IV melanoma

There are few effective treatment options available for patients with advanced melanoma. An oncolytic herpes simplex virus type 1 encoding granulocyte macrophage colony-stimulating factor (GM-CSF; Oncovex(GM-CSF)) for direct injection into accessible melanoma lesions resulted in a 28% objective response rate in a Phase II clinical trial. Responding patients demonstrated regression of both injected and noninjected lesions highlighting the dual mechanism of action of Oncovex(GM-CSF) that includes both a direct oncolytic effect in injected tumors and a secondary immune-mediated anti-tumor effect on noninjected tumors. Based on these preliminary results a prospective, randomized Phase III clinical trial in patients with unresectable Stage IIIb or c and Stage IV melanoma has been initiated. The rationale, study design, end points and future development of the Oncovex(GM-CSF) Pivotal Trial in Melanoma (OPTIM) trial are discussed in this article.

The Society for Immunotherapy of Cancer consensus statement on tumour immunotherapy for the treatment of cutaneous melanoma

Immunotherapy is associated with durable clinical benefit in patients with melanoma. The goal of this article is to provide evidence-based consensus recommendations for the use of immunotherapy in the clinical management of patients with high-risk and advanced-stage melanoma in the USA. To achieve this goal, the Society for Immunotherapy of Cancer sponsored a panel of melanoma experts—including physicians, nurses, and patient advocates—to develop a consensus for the clinical application of tumour immunotherapy for patients with melanoma. The Institute of Medicine clinical practice guidelines were used as a basis for this consensus development. A systematic literature search was performed for high-impact studies in English between 1992 and 2012 and was supplemented as appropriate by the panel. This consensus report focuses on issues related to patient selection, toxicity management, clinical end points and sequencing or combination of therapy. The literature review and consensus panel voting and discussion were used to generate recommendations for the use of immunotherapy in patients with melanoma, and to assess and rate the strength of the supporting evidence. From the peer-reviewed literature the consensus panel identified a role for interferon-α2b, pegylated-interferon-α2b, interleukin-2 (IL-2) and ipilimumab in the clinical management of melanoma. Expert recommendations for how to incorporate these agents into the therapeutic approach to melanoma are provided in this consensus statement. Tumour immunotherapy is a useful therapeutic strategy in the management of patients with melanoma and evidence-based consensus recommendations for clinical integration are provided and will be updated as warranted.

Multidrug resistance activity in human lymphocytes

The multidrug resistance gene (mdr1) is a member of the recently described ATP binding cassette (ABC) superfamily of transporters. Family members include: (1) the cystic fibrosis transmembrane conductance regulator gene; (2) the hlyB gene of bacteria, and (3) the histocompatibility antigen modifier (HAM) gene. The level of expression of mdr1 correlates with multidrug resistance (MDR), the ability of cells to efflux otherwise toxic doses of several chemotherapeutic agents. MDR activity is also associated with the efflux of cationic lipophilic compounds such as the fluorescent dye rhodamine 123. Recently it was reported that normal lymphocytes efflux rhodamine 123, suggesting that these cells possess MDR-like activity due to the expression of mdr1. In this study, using two-color flow cytometric analysis, we observed that the ability to efflux rhodamine 123 was heterogeneous among human lymphocyte subsets in the order of CD8 greater than CD4 greater than CD2O. Rhodamine 123 efflux and accumulation in lymphocytes was sensitive to the known MDR reversing agents, verapamil and Solutol HS 15. Collectively, these data suggest that an MDR-like transport system is present in normal lymphocytes and may be important for trafficking of molecules involved in lymphocyte function.

Prognostic significance of DNA aneuploidy in stage I cutaneous melanoma.

The prognostic significance of DNA aneuploidy was studied retrospectively in 177 Stage I cutaneous melanomas. DNA content was determined by flow cytometry of propidium iodide-stained nuclei recovered from formalin-fixed, paraffin-embedded material. Of 162 evaluable histograms, 124 were diploid, 35 aneuploid, and 3 tetraploid. Aneuploidy strongly correlated with established predictors of unfavorable prognosis, namely, thickness p <.005, level p < 0.005, ulceration p < 0.005, and presence of vertical growth phase p < 0.02. Overall, aneuploidy was strongly correlated with recurrence (p < 0.005) and shorter disease-free survival (p < 0.0001). Aneuploidy was an independent predictor of recurrence for tumors < 1.5 mm thick (p < 0.0001) and

Mutant HSP70 Reverses Autoimmune Depigmentation in Vitiligo

3 mm thick (p = 0.031). For melanomas 1.5–2.9 mm thick, aneuploid tumors had a 27% higher recurrence rate than diploid tumors (63% vs. 36%). This was not statistically significant (p = 0.247). In a multivariate analysis of common predictors stratified by thickness, DNA aneuploidy was the most significant independent parameter (p < 0.002). DNA content appears to be an important stratification parameter for Stage I cutaneous melanoma.

TroVax, a recombinant modified vaccinia Ankara virus encoding 5T4: Lessons learned and future development

Multidrug resistance (MDR) is the phenomenon in which cultured tumor cells selected for resistance to one chemotherapeutic agent simultaneously acquire resistance to several apparently unrelated drugs. MDR in tumor cells is associated with the over-expression of P-glycoprotein, an ATP-dependent cell-membrane transport molecule. P-glycoprotein is also expressed in several normal tissues but its physiological role(s) is unknown. We recently observed that a hierarchy of MDR-like activity exists among human peripheral blood lymphocytes in the order CD8>CD4>CD20 (cytoxic/suppressor T cells, helper T cells and B cells respectively). In this study, we report that natural killer (NK) cells also express MDR-like activity. This activity could be inhibited with verapamil or solutol HS-15, two agents that reverse MDR in tumor cells. These, and four additional reversing agents, were used to investigate the possible role of P-glycoprotein in NK cells. We observed that at 10% of their IC50, five of six reversing agents inhibited NK-cell-mediated cytotoxicity; at higher (but non-toxic) doses, all six agents were inhibitory. These data suggest that NK-cell-mediated cytotoxicity may require the functional expression of an efflux molecule similar or identical to P-glycoprotein.

Survival after repeat hepatic resection for recurrent colorectal hepatic metastases.

Vitiligo can be reversed through immune targeting with mutant heat shock protein 70. New Treatment Makes Vitiligo Beat It Whether your grant application is due, you have a paper that needs to be submitted, or your patient load is too high, medical science is not a relaxing profession. High stress is known to negatively affect your health at both the whole body and cellular level. One way the body responds to cellular stressors is through the induction of heat shock proteins (HSPs). Now, Mosenson et al. suggest that mutant HSP70 could be a potential treatment for autoimmune vitiligo. The authors noticed that mutant inducible HSP70 (HSP70i) could prevent T cell–mediated depigmentation in a mouse model of vitiligo, perhaps by shifting dendritic cells from an inflammatory to a regulatory phenotype. Moreover, a DNA vaccine of the mutant HSP70i could be used therapeutically to partially restore pigmentation in a second model of depigmentation. The authors then took these studies into ex vivo human skin, showing that their mutant HSP70i could prevent the disease-related shift from quiescent to effector T cell phenotype. Although these observations still need to be translated into the clinic, they form the basis for a new potential treatment for autoimmune vitiligo. Vitiligo is an autoimmune disease characterized by destruction of melanocytes, leaving 0.5% of the population with progressive depigmentation. Current treatments offer limited efficacy. We report that modified inducible heat shock protein 70 (HSP70i) prevents T cell–mediated depigmentation. HSP70i is the molecular link between stress and the resultant immune response. We previously showed that HSP70i induces an inflammatory dendritic cell (DC) phenotype and is necessary for depigmentation in vitiligo mouse models. Here, we observed a similar DC inflammatory phenotype in vitiligo patients. In a mouse model of depigmentation, DNA vaccination with a melanocyte antigen and the carboxyl terminus of HSP70i was sufficient to drive autoimmunity. Mutational analysis of the HSP70i substrate-binding domain established the peptide QPGVLIQVYEG as invaluable for DC activation, and mutant HSP70i could not induce depigmentation. Moreover, mutant HSP70iQ435A bound human DCs and reduced their activation, as well as induced a shift from inflammatory to tolerogenic DCs in mice. HSP70iQ435A-encoding DNA applied months before spontaneous depigmentation prevented vitiligo in mice expressing a transgenic, melanocyte-reactive T cell receptor. Furthermore, use of HSP70iQ435A therapeutically in a different, rapidly depigmenting model after loss of differentiated melanocytes resulted in 76% recovery of pigmentation. Treatment also prevented relevant T cells from populating mouse skin. In addition, ex vivo treatment of human skin averted the disease-related shift from quiescent to effector T cell phenotype. Thus, HSP70iQ435A DNA delivery may offer potent treatment opportunities for vitiligo.

The use of radioisotope combined with isosulfan blue dye is not superior to radioisotope alone for the identification of sentinel lymph nodes in patients with breast cancer

There has been renewed interest in developing vaccine and immunotherapy for the treatment of cancer. The oncofetal antigen, 5T4, is a surface glycoprotein that is expressed on a variety of human adenocarcinomas but rarely on normal tissue. 5T4 plays an important role in tumor progression and metastasis. The expression patterns and functional role in the metastatic process suggest that 5T4 is a good target for vaccine development. A modified vaccinia virus Ankara (MVA) encoding human 5T4 (designated TroVax) demonstrated therapeutic effects in murine tumor models and human T cells recognized 5T4 epitopes in an HLA-restricted manner. The TroVax vaccine has subsequently been evaluated in clinical trials targeting patients with colorectal cancer, renal cell carcinoma and hormone refractory prostate cancer. Herein, we review the results of these clinical studies, discuss the lessons learned through these trials and provide some insight into the future development of TroVax as a cancer vaccine.

TroVax® vaccine therapy for renal cell carcinoma

BACKGROUND This is a retrospective clinical study done to examine survival of patients undergoing repeat hepatic resection for recurrent colorectal hepatic metastases. METHODS The records of 131 patients undergoing hepatic resection for metastatic colorectal cancer were reviewed. Curative resection was performed in 107 of these patients. Thirty-one experienced recurrences confined to the liver. Thirteen (13 of 107, 12%) of them underwent resection and make up the study population. RESULTS The eight men (62%) and five women (38%) had a median age of 60 years (range, 32 to 75 years). In 30% of patients recurrence developed near the original resection site. In 70% the recurrences were remote from the original site. The patients underwent a total of six wedge resections, two left lateral segmentectomies, three right lobectomies, and two trisegmentectomies. Average blood loss was 2995 cc; average hospital stay was 17.2 days. Morbidity was 23% (3 of 13); mortality was 8% (1 of 13). Four patients died of recurrent disease, with a mean disease-free survival of 9.7 months (median, 7.5 months; range, 3 to 21 months) and mean total survival of 39 months (median, 24 months; range, 8 to 99 months). One of these patients had a second recurrence resected at month 21 and lived an additional 78 months. Seven patients were alive with no evidence of disease, with a mean follow-up time of 34.9 months (median, 14 months; range, 1 to 186 months). Actual 5-year survival was 23% (3 of 13). Actual disease-free 5-year survival was 15% (2 of 13). CONCLUSIONS In properly selected patients morbidity, mortality, and survival after repeat resection are similar to those after initial resection.