Michael Pan

Elevated rates of transaminitis during ipilimumab therapy for metastatic melanoma.

Melanoma is the deadliest form of skin cancer. Ipilimumab, a novel immunotherapy, is the first treatment shown to improve survival in patients with metastatic melanoma in large randomized controlled studies. The most concerning side effects reported in clinical studies of ipilimumab fall into the category of immune-related adverse events, which include enterocolitis, dermatitis, thyroiditis, hepatitis, hypophysitis, uveitis, and others. During the course of routine clinical care at Mount Sinai Medical Center, frequent hepatotoxicity was noted when ipilimumab was administered at a dose of 3 mg/kg according to Food and Drug Administration (FDA) guidelines. To better characterize these adverse events, we conducted a retrospective review of the first 11 patients with metastatic melanoma treated with ipilimumab at the Mount Sinai Medical Center after FDA approval. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) elevation, as defined by the National Cancer Institute’s Common Terminology Criteria for Adverse Events, each occurred in six of 11 cases (≥grade 1), a notably higher frequency than could be expected on the basis of the FDA licensing study where elevations were reported in 0.8 and 1.5% of patients for AST and ALT, respectively. Grade 3 elevations in AST occurred in three of 11 patients as compared with 0% in the licensing trial. All cases of transaminitis resolved when ipilimumab was temporarily withheld without administration of immunosuppressive medication. During routine clinical care of late-stage melanoma patients with ipilimumab, physicians should monitor patients closely for hepatotoxicity and be aware that toxicity rates may differ across populations during ipilimumab therapy.

Dissection of Immune Gene Networks in Primary Melanoma Tumors Critical for Antitumor Surveillance of Patients with Stage II–III Resectable Disease

Patients with resected stage II-III cutaneous melanomas remain at high risk for metastasis and death. Biomarker development has been limited by the challenge of isolating high-quality RNA for transcriptome-wide profiling from formalin-fixed and paraffin-embedded (FFPE) primary tumor specimens. Using NanoString technology, RNA from 40 stage II-III FFPE primary melanomas was analyzed and a 53-immune-gene panel predictive of non-progression (area under the curve (AUC)=0.920) was defined. The signature predicted disease-specific survival (DSS P<0.001) and recurrence-free survival (RFS P<0.001). CD2, the most differentially expressed gene in the training set, also predicted non-progression (P<0.001). Using publicly available microarray data from 46 primary human melanomas (GSE15605), a coexpression module enriched for the 53-gene panel was then identified using unbiased methods. A Bayesian network of signaling pathways based on this data identified driver genes. Finally, the proposed 53-gene panel was confirmed in an independent test population of 48 patients (AUC=0.787). The gene signature was an independent predictor of non-progression (P<0.001), RFS (P<0.001), and DSS (P=0.024) in the test population. The identified driver genes are potential therapeutic targets, and the 53-gene panel should be tested for clinical application using a larger data set annotated on the basis of prospectively gathered data.

Herpes simplex virus oncolytic vaccine therapy in melanoma

Importance of the field: Advanced melanoma is a devastating disease with a five year survival for Stage IV disease of 10 – 20% and a median survival of 6 – 18 months depending on sub-stage. Current FDA approved therapies demonstrate limited response rates, few complete remissions and no proven survival benefit. New therapies are clearly needed. JSI/34.5-/47-/GM-CSF is a herpes simplex virus-1 (OncoVEXGM-CSF) oncolytic vaccine therapy designed to induce local and systemic anti-tumor immune responses. Areas covered in this review: Evolution of current herpes simplex virus oncolytic vaccines from preclinical to clinical studies from 1994 to 2010. What the reader will gain: Preclinical studies have shown that herpes simplex virus-1 oncolytic vaccines generate local tumor destruction through the lytic action of the virus and local and systemic immune responses. Phase I studies demonstrated limited toxicities with no neurotoxicty. Phase II studies demonstrated durable regressions in patients with metastatic melanoma. A Phase III trial in melanoma is ongoing to determine clinical effectiveness, and a Phase III trial in head and neck cancer will initiate during 2010. Take home message: JSI/34.5-/47-/GM-CSF is a new generation herpes simplex virus-1 oncolytic vaccine that demonstrates direct tumor lysis and systemic immune responses. Early clinical studies have yielded preliminary evidence of activity.

Requirement for Innate Immunity and CD90+ NK1.1− Lymphocytes to Treat Established Melanoma with Chemo-Immunotherapy

Moskalenko, Pan, and colleagues show in a B16 melanoma model that tumor clearance from the combined regimen of cytotoxic doses of cyclophosphamide and an antibody targeting melanoma differentiation antigen tyrosine-related protein 1 requires Fcγ receptors and innate CD90+NK1.1− lymphocytes, not classical NK cells. We sought to define cellular immune mechanisms of synergy between tumor-antigen–targeted monoclonal antibodies and chemotherapy. Established B16 melanoma in mice was treated with cytotoxic doses of cyclophosphamide in combination with an antibody targeting tyrosinase-related protein 1 (αTRP1), a native melanoma differentiation antigen. We find that Fcγ receptors are required for efficacy, showing that antitumor activity of combination therapy is immune mediated. Rag1−/− mice deficient in adaptive immunity are able to clear tumors, and thus innate immunity is sufficient for efficacy. Furthermore, previously treated wild-type mice are not significantly protected against tumor reinduction, as compared with mice inoculated with irradiated B16 alone, consistent with a primarily innate immune mechanism of action of chemo-immunotherapy. In contrast, mice deficient in both classical natural killer (NK) lymphocytes and nonclassical innate lymphocytes (ILC) due to deletion of the IL2 receptor common gamma chain IL2γc−/−) are refractory to chemo-immunotherapy. Classical NK lymphocytes are not critical for treatment, as depletion of NK1.1+ cells does not impair antitumor effect. Depletion of CD90+NK1.1− lymphocytes, however, both diminishes therapeutic benefit and decreases accumulation of macrophages within the tumor. Tumor clearance during combination chemo-immunotherapy with monoclonal antibodies against native antigen is mediated by the innate immune system. We highlight a novel potential role for CD90+NK1.1− ILCs in chemo-immunotherapy. Cancer Immunol Res; 3(3); 296–304. ©2015 AACR.

Oncolytic virus therapy for cancer

The use of oncolytic viruses to treat cancer is based on the selection of tropic tumor viruses or the generation of replication selective vectors that can either directly kill infected tumor cells or increase their susceptibility to cell death and apoptosis through additional exposure to radiation or chemotherapy. In addition, viral vectors can be modified to promote more potent tumor cell death, improve the toxicity profile, and/or generate host antitumor immunity. A variety of viruses have been developed as oncolytic therapeutics, including adenovirus, vaccinia virus, herpesvirus, coxsackie A virus, Newcastle disease virus, and reovirus. The clinical development of oncolytic viral therapy has accelerated in the last few years, with several vectors entering clinical trials for a variety of cancers. In this review, current strategies to optimize the therapeutic effectiveness and safety of the major oncolytic viruses are discussed, and a summary of current clinical trials is provided. Further investigation is needed to characterize better the clinical impact of oncolytic viruses, but there are increasing data demonstrating the potential promise of this approach for the treatment of human and animal cancers.

Instructional video for teaching venepuncture.

Safe venepuncture technique is a critical skill for health care professionals, to avoid accidental occupational injury. This study investigates whether watching an instructional video improves medical students’ ability to perform venepuncture safely.

Defining the role of CD2 in disease progression and overall survival among patients with completely resected stage-II to -III cutaneous melanoma

BACKGROUND Accurate assessment of prognosis remains clinically challenging in stage II to III cutaneous melanoma. Studies have implicated CD2 in immune surveillance, T-cell activation, and antitumor immunity, but its role in melanoma progression warrants further investigation. OBJECTIVE We sought to investigate the prognostic role of CD2 in primary cutaneous melanoma. METHODS Patients with American Joint Committee on Cancer stage II and III cutaneous melanoma were identified by retrospective review of dermatopathology databases from 2001 to 2010 at Mount Sinai Medical Center and Geisinger Medical Center. Additional patients were provided by New York University Medical Center based on retrospective review and tissue availability. Immunohistochemistry was performed on tumors from 90 patients with known recurrence status and documented follow-up. RESULTS Primary tumors from patients who developed recurrent disease had fewer CD2(+) cells (P = .0003). In multivariable analyses including standard clinicopathologic predictors, CD2 was an independent predictor of disease recurrence (P = .008) and overall survival (P = .007). CD2 count correlated with characterization of tumor-infiltrating lymphocytes (P = .0004). Among the intermediate prognosis group of patients with nonbrisk tumor-infiltrating lymphocytes, CD2 count was predictive of disease recurrence (P = .0006) and overall survival (P = .0318). LIMITATIONS Our retrospective design may have resulted in incomplete representation of patients lacking documented follow-up. CONCLUSIONS CD2 may be an independent predictor of disease recurrence and overall survival among patients with primary cutaneous melanoma.

Frequency of Monotherapy versus Combination Therapy in Reported Cases of Infections Occurring in the Setting of Biologic Agents

The purpose of this work was to determine the frequency with which concomitant immunosuppressive medications were used in a systemic review of reported cases of infection occurring in the setting of biologic therapy. A Pub Med search was conducted using the term “infection” combined with “biologic” and specific biologic drug names to identify case reports and case series written in English documenting patients who were diagnosed with an infection while being treated with a biologic agent. Demographic information, biologic medication, treatment indication, and patient outcomes, as well as information regarding the use of concomitant immunosuppressive therapies, were recorded. A total of 246 patients from 148 case reports and 20 case series met inclusion criteria and were evaluated. Among reported cases of infection occurring in the setting of biologic therapy, 69.9% were being treated with ≥1 other immunosuppressive medication. Of patients receiving concomitant therapies, corticosteroids (56.4%) and methotrexate (53.5%) were taken most frequently. Bacteria composed the majority of infections in this review (57.7%) with nonmycobacteria implicated in 38.6% of cases and mycobacteria in 19.1% of patients. In this cohort, patients receiving tumor necrosis factor-α inhibitors with other immunosuppressive medications experienced 2.67 times more reported nonserious infections (outpatient management), 2.33 times more reported hospitalizations, and 2.75 times more deaths than patients receiving biologic monotherapy. Infection risk among patients on biologic therapy is significantly confounded by the widespread use of concomitant immunosuppressive medication(s) and may be overestimated, particularly for patients who take biologic drugs as monotherapy.

Biologic Drugs and Malignancy: A Literature Review Examining the Impact of Concomitant Immunosuppressive Medications

The objective of this work was to conduct a systematic review of the frequency with which concomitant immunosuppressive medication(s) are used in patients receiving biologics who develop malignancy. We conducted a PubMed search using the term “malignancy” and specific cancers combined with “biologic” and specific biologic drug names to identify case reports and case series written in English documenting patients who were diagnosed with malignancy while being treated with a biologic agent. Demographic information, biologic medication including treatment indication, malignancy type, time to malignancy diagnosis, patient outcome, and information regarding concomitant usage of immunosuppressive medication(s) were recorded. A total of 210 patients from 78 case reports and 21 case series met inclusion criteria and were evaluated. Among patients who developed malignancy while on biologic therapy, 64.8% were simultaneously being treated with ≥1 other immunosuppressive medication. A median time of 12 months was observed between initiation of biologic therapy and development of disease in this cohort. Methotrexate (28.6%) and azathioprine (23.8%) were the most common concomitant therapies. When compared with patients receiving biologic monotherapy, patients who received biologics with other immunosuppressive medications experienced 3.21 times more deaths because of malignancy with an odds ratio of 2.12 (95% CI, 1.07–4.19). The risk of malignancy among patients receiving biologic therapy is significantly confounded by the prevalent use of concomitant immunosuppressive medication(s). This risk may be overestimated, particularly for patients who take biologic drugs as monotherapy.

Abstract A43: Therapeutic efficacy of antitumor monoclonal antibodies combined with chemotherapy depends on innate immunity and NK1.1- innate lymphoid cells.

Combination regimens incorporating chemotherapy and anti-tumor monoclonal antibodies are in wide clinical use but mechanisms of action are unknown. A better mechanistic understanding would enhance clinical protocols. We treated established melanomas with cyclophosphamide (CY) in combination with an antibody targeting tyrosinase related protein 1 (TRP1), a melanoma differentiation antigen. Therapeutic activity is immune mediated as Fc gamma receptors are required for efficacy. Immune responses can be innate or adaptive and, using Rag 1-/- mice deficient in B and T lymphocytes, we find that the innate immune system is sufficient for tumor clearance. Classic effector cells of the innate immune system include lymphocytes, of which the largest population is NK1.1+ natural killer (NK) cells, and macrophages. NK cells, surprisingly, are not critical as depletion of NK1.1+ cells did not significantly impair anti-tumor effect. In contrast, elimination of non-classical NK1.1- innate lymphocytes, through deletion of the Interleukin 2 (IL2) receptor common gamma chain required for their development, or depletion via antibody targeting pan lymphocyte marker Thy1.2 in Rag 1-/- mice, impairs efficacy of combination therapy. Non-classical NK1.1-Thy1.2+ innate lymphocytes have been implicated in leukocyte infiltration into tissues. We find that depletion of Thy1.2+ cells diminishes entry of Thy 1.2- leukocytes into melanomas treated with chemotherapy and alters the phenotype of infiltrating myeloid cells. Thus, our data highlights a novel role for non-classical innate lymphocytes in the treatment of solid malignancies with monoclonal antibody and chemotherapy. Citation Format: Marina Moskalenko, Michael Pan, Daigo Hashimoto, Arthur Mortha, Sebastian G. Bernardo, Marylene Leboeuf, Alan Houghton, Jedd Wolchok, Steven Burakoff, Miriam Merad, Yvonne M. Saenger. Therapeutic efficacy of antitumor monoclonal antibodies combined with chemotherapy depends on innate immunity and NK1.1- innate lymphoid cells. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr A43.