Tasha Hughes

Current status of granulocyte–macrophage colony-stimulating factor in the immunotherapy of melanoma

In 2012, it was estimated that 9180 people in the United States would die from melanoma and that more than 76,000 new cases would be diagnosed. Surgical resection is effective for early-stage melanoma, but outcomes are poor for patients with advanced disease. Expression of tumor-associated antigens by melanoma cells makes the disease a promising candidate for immunotherapy. The hematopoietic cytokine granulocyte–macrophage colony-stimulating factor (GM-CSF) has a variety of effects on the immune system including activation of T cells and maturation of dendritic cells, as well as an ability to promote humoral and cell-mediated responses. Given its immunobiology, there has been interest in strategies incorporating GM-CSF in the treatment of melanoma. Preclinical studies with GM-CSF have suggested that it has antitumor activity against melanoma and can enhance the activity of anti-melanoma vaccines. Numerous clinical studies have evaluated recombinant GM-CSF as a monotherapy, as adjuvant with or without cancer vaccines, or in combination with chemotherapy. Although there have been suggestions of clinical benefit in some studies, results have been inconsistent. More recently, novel approaches incorporating GM-CSF in the treatment of melanoma have been evaluated. These have included oncolytic immunotherapy with the GM-CSF–expressing engineered herpes simplex virus talimogene laherparepvec and administration of GM-CSF in combination with ipilimumab, both of which have improved patient outcomes in phase 3 studies. This review describes the diverse body of preclinical and clinical evidence regarding use of GM-CSF in the treatment of melanoma.

Mutant HSP70 Reverses Autoimmune Depigmentation in Vitiligo

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.

Critical analysis of an oncolytic herpesvirus encoding granulocyte-macrophage colony stimulating factor for the treatment of malignant melanoma

Oncolytic viruses that selectively lyse tumor cells with minimal damage to normal cells are a new area of therapeutic development in oncology. An attenuated herpesvirus encoding the granulocyte-macrophage colony stimulating factor (GM-CSF), known as talimogene laherparepvec (T-VEC), has been identified as an attractive oncolytic virus for cancer therapy based on preclinical tumor studies and results from early-phase clinical trials and a large randomized Phase III study in melanoma. In this review, we discuss the basic biology of T-VEC, describe the role of GM-CSF as an immune adjuvant, summarize the preclinical data, and report the outcomes of published clinical trials using T-VEC. The emerging data suggest that T-VEC is a safe and potentially effective antitumor therapy in malignant melanoma and represents the first oncolytic virus to demonstrate therapeutic activity against human cancer in a randomized, controlled Phase III study.

Is BMI associated with post-operative complication risk among patients undergoing major abdominal surgery for cancer? A systematic review

We systematically reviewed 118 studies comparing peri‐operative outcomes among obese and non‐obese patients. Obesity was associated with longer operative time in 60% of available studies. Just 35.8% of studies that evaluated overall morbidity identified high morbidity in obese patients. Lymph node yield or surgical margin status, was only affected by obesity in 19.6% of studies. In this review obesity was frequently found to have no effect on peri‐operative and oncologic outcomes.

Metastasectomy following incomplete response to high-dose interleukin-2

To evaluate our experience with metastasectomy following partial response or stable disease after treatment with high‐dose interleukin‐2 (HD IL‐2).

Combination immunotherapy with anti-CTLA-4 and interleukin-2 redirects regulatory T cells into tumor-draining lymph nodes and expands anti-tumor CD8+ T cells in the tumor microenvironment

Meeting abstracts Monotherapy with Ipilimumab (anti-CTLA-4 antibody) and monotherapy with IL-2 (T cell stimulating cytokine) are approved for the treatment of metastatic melanoma. Combination immunotherapy has been suggested as a more potent regimen but has not been sufficiently investigated. We

The Use of Oncolytic Herpesvirus for the Treatment of Cancer

Oncolytic immunotherapy is a new form of cancer treatment that utilizes native or genetically modified viruses to directly infect tumor cells. These viruses selectively replicate in tumor cells and may induce systemic antitumor immune responses. To date, the herpesviruses have been the most widely evaluated for clinical development as a cancer therapeutic. A modified herpesvirus encoding human granulocyte-macrophage colony-stimulating factor (GM-CSF) has been named talimogene laherparepvec (T-VEC) and has shown clinical benefits in a randomized Phase III clinical trial in patients with advanced melanoma. This chapter will review the basic mechanisms of oncolytic viruses, describe the basic biology of herpesviruses, and discuss the clinical results of trials with T-VEC. Future directions and priorities for clinical development of T-VEC and other oncolytic viruses will be discussed.

Role of dose selection in successful interleukin-2 immunotherapy: solving the Goldilock’s Complex

Background The results of multiple IL-2 clinical trials (using a range of doses) have shown similar trends, in which IL-2 immunotherapy leads to an objective response in 15-20% of patients and complete response in 5-10%. Importantly, the majority (> 80%) of patients with a complete response maintain long-term responses. However, why only a small proportion of patients attain a complete response at any dose is unknown. We hypothesized that the dose of IL-2 utilized, differentially targets CD8+ effector versus CD4+ regulatory T cells based on patient-specific characteristics, and that an optimal IL-2 dose may be needed to achieve therapeutic benefit.

The role of surgery following incomplete response to high-dose IL-2 (HD IL-2)

Background Surgical resection of metastatic cancer is beneficial in select patients with cancer. HD IL-2 is an FDA approved immunotherapy for the treatment of patients with melanoma or renal cell carcinoma. IL-2 induces a complete response (CR) in 4-10% of patients while an additional 10% of patients have a partial response (PR). While not frequently reported, our experience suggests an additional 20% of patients have a stable response (SD) to therapy. The subsequent management of patients with an incomplete response, either partial or stable, has not been well studied and we sought to determine if metastasectomy might have ar ole in this setting. Methods 305 patients with metastatic renal cell carcinoma or melanoma treated with IL-2 therapy over a 12-year period were reviewed. Age, response and survival data were available for 215 patients. Response was determined using standard RECIST criteria and patients with partial response (PR) or stable disease (SD) were considered incomplete responders to IL-2. Patients with an incomplete response were evaluated by a surgical oncologist. Surgical complete response (sCR) was defined as complete surgical resection of a single or multiple sites of disease following IL-2 therapy that rendered patients free of disease. Overall survival was estimated analyzed using Kaplan-Meier curves and compared between groups using the log-rank test. Results The objective response rate (PR + CR) to HD IL-2 in this cohort was 13.6%. An additional 24.4% of patients had SD following their initial course of therapy. Median survival of all treated patients was 16.8 months. Incomplete response to IL-2 does confer an improvement in overall survival compared to patients with progressive disease (median survival 38.2 v. 7.9 months). Eighty-one patients had an incomplete response (PR + SD) to IL-2, fifteen of whom underwent subsequent metastasectomy. Patients undergoing metastasectomy had improved overall survival compared to patients with an incomplete response that did not undergo subsequent surgery (38.2 months v. median not reached in surgical patients, p=0.026). Of patients treated surgically following HD IL-2 12 patients were alive at the end of follow-up with follow-up ranging from 15 months to 96 months. Conclusion The addition of surgical resection may improve upon the survival benefit in select patients with incomplete response to HD IL-2. These findings are biased by patient selection, but our results support the rationale for a prospective trial to determine the role of metastasectomy following incomplete response to IL-2 therapy. Additionally, we are interested in understanding how surgical resection following immunotherapy may reset immunologic balance in patients with metastatic cancer.

Clinical benefit of high dose IL-2 (HD IL-2) therapy: evidence for improved overall survival in patients with stable disease

Background HD IL-2 is an approved immunotherapy for advanced melanoma and renal cell carcinoma with a reported objective response rate (ORR) up to 20%. Patients with stable disease (SD) following treatment are not considered objective responders and thus are not included in reported response rates. Since the initial reports of IL-2 our understanding of the delayed pharmacokinetics of immunotherapy has improved. The purpose of this study is to report the clinical outcomes for patients with stable response to HD IL-2. Methods A retrospective chart review of 305 patients diagnosed with metastatic renal cell carcinoma or melanoma and treated with HD IL-2 therapy over a 12-year period was conducted. Age, response to HD IL-2 (based on RECIST criteria) and survival data were available in 215 patients at the time of analysis. Survival analysis was conducted on all patients for whom complete data was available and Kaplan-Meier curves were generated based on overall survival. Results Among the 215 patients with complete data, 62% had progressive disease (PD), 24% had SD and the objective response rate was 14%. Median overall survival was 16.8 months among all 215 patients. Patients with a PR or CR (median survival not reached in the study period) had significantly prolonged survival than the remaining patients (median survival 13.9 months, log-rank p < 0.01). Patients with SD (median survival of 38.2 months) had improved survival compared to patients with progressive disease (median survival of 7.9 months, log-rank p< 0.01). Discussion The IL-2 literature has focused on partial or complete responders when reporting objective response rates. In our data, as well as elsewhere in the literature, there are a large number of patients who have as table response to HD IL-2 that have not been included in the ORR. Our data supports a significant survival benefit associated with stable disease following IL-2, which suggests that HD IL-2 may result in a clinical benefit in a larger number of patients than has previously been reported. Consideration of ad isease control rate (DCR) inclusive of objective responders and stable responses may be more appropriate to better define the clinical benefit of IL-2.