Colette Pameijer

Conversion of a tumor-binding peptide identified by phage display to a functional chimeric T cell antigen receptor.

Adoptive transfer of ex vivo expanded tumor-specific T cells is a promising therapeutic modality for promoting or augmenting antitumor immunity. Several groups, including ours, are developing antigen receptor gene transfer strategies as a means of generating effector cells for adoptive therapy. Chimeric antigen receptors (CARs) have been described that use single-chain antibodies or cytokine ligands as tumor targeting domains. Here, we describe the capacity of a tumor-binding peptide identified by phage display combinatorial library screening to serve as a CAR targeting domain. A phage library-selected high-affinity 12-mer peptide (Bpep) specific for alpha(v) beta(6) integrin (αvβ6) was chosen for these studies. Primary human T cells were genetically modified to express the Bpep-CAR consisting of an αvβ6-specific peptide and human IgG4 hinge-Fc extracellular domain fused to the cytoplasmic tail of CD3-ζ. T cell expression of the Bpep-CAR was assessed by Western blot analysis, and trafficking of the Bpep-CAR to the cell surface was demonstrated by flow cytometry. Functionally, Bpep-CAR redirected cytotoxic T lymphocytes specifically kill integrin αvβ6+ ovarian tumor targets, and are activated for interferon gamma secretion. Our data suggest that large new repertoires of tumor-specific T cell antigen receptor transgenes might be available through merging combinatorial peptide libraries with CAR construct design.

Improved survival and complete response rates in patients with advanced melanoma treated with concurrent ipilimumab and radiotherapy versus ipilimumab alone

ABSTRACT There is a growing body of evidence supporting the synergistic roles of radiotherapy and immunotherapy in the treatment of malignancy. Published case studies of the abscopal effect have been reported with the use of ipilimumab and radiotherapy in metastatic melanoma, but evidence supporting the routine use of this combination of therapy is limited. We conducted a retrospective analysis to evaluate patients treated with ipilimumab for advanced melanoma at a single institution from May 2011 to June 2015. Patients were grouped into those who had received concurrent radiotherapy while on ipilimumab (Ipi-RT), and those who did not. We then evaluated the treatment response following completion of ipilimumab. A total of 101 patients received ipilimumab in the prespecified time frame. 70 received Ipi-RT and 31 received ipilimumab without concurrent radiotherapy. Median overall survival (OS) was significantly increased in the concurrent Ipi-RT arm at 19 months vs. 10 months for ipilimumab alone (p = 0.01). Median progression free survival (PFS) was marginally increased in the Ipi-RT group compare with the ipilimumab alone group (5 months vs. 3 months, p = 0.20). Rates of complete response (CR) were significantly increased in the Ipi-RT group vs. ipilimumab alone (25.7% vs. 6.5%; p = 0.04), and rates of overall response (OR) in the groups were 37.1% vs. 19.4% (p = 0.11). No increase in toxicities was observed in the Ipi-RT group compare with ipilimumab alone. Prospective trials are needed to further clarify the role of radiotherapy with ipilimumab, but these encouraging preliminary observations suggest that this combination can induce more durable responses to immunotherapy.

Bowel obstruction in patients with metastatic cancer: Does intervention influence outcome?

AbstractBackground: Both surgical and nonsurgical options are available to treat bowel obstruction in patients with metastatic cancer. The goal is straightforward: to restore bowel patency and palliate the symptoms of obstruction. Yet the most appropriate management is often a challenging decision. Aim of the Study: We sought to review our experience in managing patients with metastatic cancer and bowel obstruction. Methods: A retrospective review was performed to identify all patients admitted at University of Wisconsin Hospital between 1993 and 2000 with the diagnoses of both bowel obstruction and metastatic cancer. Demographic data, type of management, postoperative complications, and outcome were analyzed. Results: A total of 114 patients with primarily colorectal or gynecologic malignancies were identified. Patients’ first bowel obstructions were managed in one of two ways: (1) definitive surgical intervention (n=47), or (2) conservative management (n=67). The median overall survival was 3 mo for the entire study group. There was no significant difference in overall or obstruction-free survival based on management, presence of recurrent bowel obstruction, or type of primary cancer. The only factor that was significant in predicting poor overall survival included a disease-free interval of less than 1 yr (time of diagnosis of primary cancer to time of bowel obstruction, p=0.002). Conclusions: Bowel obstruction in patients with metastatic cancer is a terminal event, with a 3-mo median survival. Because there is no difference in overall or obstruction-free survival based on management, the treatment for palliation of bowel obstruction in patients with metastatic cancer should be individualized.

Malignant melanoma—The cradle of anti-neoplastic immunotherapy

One of the defining characteristics of the malignant phenotype is the ability to evade the host immune system. Immunotherapy as a treatment modality represents a new dawn in the way we think about the treatment of a variety of malignancies. The story of immunotherapy traces its roots to its relationship with malignant melanoma. In this article, we review the intertwined history of immunotherapy and melanoma, including the early significant history, a discussion on immune mechanisms, resistance, local and systemic immunotherapeutic modalities, and speculate on possible novel future treatment options.

Primary Extrauterine Endometrial Stromal Cell Sarcoma: A Case and Review

BackgroundExtrauterine endometrial stromal sarcoma (ESS) is a rare neoplasm. Little is known about its pathophysiology or best treatment approach.CaseWe are describing a case of extrauterine ESS in a 70-year-old woman on hormone replacement therapy and with a history of endometriosis. We also present a brief review of the literature on ESS and its relationship to endometriosis and hormonal therapy.ConclusionsComplete resection should remain the treatment of choice for ESS. Unresectable or metastatic low-grade ESS may respond well to progestin therapy, but outcomes of high-grade ESS tend to be poor.

Nanoliposomal delivery of cytosolic phospholipase A2 inhibitor arachidonyl trimethyl ketone for melanoma treatment

Drug resistance and toxicity are major limitations of cancer treatment and frequently occurs during melanoma therapy. Nanotechnology can decrease drug resistance by improving drug delivery, with limited toxicity. This study details the development of nanoparticles containing arachidonyl trifluoromethyl ketone (ATK), a cytosolic phospholipase A2 inhibitor, which can inhibit multiple key pathways responsible for the development of recurrent resistant disease. Free ATK is toxic, limiting its efficacy as a therapeutic agent. Hence, a novel nanoliposomal delivery system called NanoATK was developed, which loads 61.7% of the compound and was stable at 4oC for 12 weeks. The formulation decreased toxicity-enabling administration of higher doses, which was more effective at inhibiting melanoma cell growth compared to free-ATK. Mechanistically, NanoATK decreased cellular proliferation and triggered apoptosis to inhibit melanoma xenograft tumor growth without affecting animal weight. Functionally, it inhibited the cPLA2, AKT, and STAT3 pathways. Our results suggest the successful preclinical development of a unique nanoliposomal formulation containing ATK for the treatment of melanoma.

The Role of Intravenous Fluids and Enteral or Parenteral Nutrition in Patients with Life-limiting Illness

The decision of whether or not to use artificial nutrition or hydration is one with which many health care providers, patients, and families struggle. These decisions are particularly challenging in the setting of life-limiting illness, which is often associated with a prolonged decline because of medical advances in these patient populations. A patient-centered and family-centered approach helps to attain high-quality care in this special population.

Isolated limb infusion as a treatment option for malignant granular cell tumour

A 54-year-old man presented with a painful lesion on the right posterior calf with MRI identifying a 5 cm lesion in the medial head of the gastrocnemius. He underwent wide local excision of the tumour, and the final pathology was consistent with atypical granular cell tumour. Three years later, he developed a recurrent right popliteal mass. Complete staging workup also identified multiple lung nodules and a caecal polyp that were consistent with metastatic granular cell tumour. He was started on pazopanib and deemed a poor candidate for palliative resection due to encasement of the popliteal vessels. The patient refused above-the-knee amputation (AKA) at that point and was evaluated for isolated limb infusion as an alternative. He received three cycles of isolated limb infusion within a 2-year period and achieved good response from the first two cycles. He underwent AKA 4 years after his diagnosis of malignant granular cell tumours and is currently doing well.

Indocyanine green and fluorescence lymphangiography for sentinel node identification in patients with melanoma

BACKGROUND Infrared fluorescence imaging with indocyanine green (ICG) is a novel method for sentinel node localization. Our objective was to assess ICG and fluorescence imaging for preoperative and intraoperative utility. METHODS 87 eligible patients participated in this prospective study. All patients received injection of ICG dye in addition to both methylene blue and 99mTc. Each sentinel node was assessed for the presence of each dye. RESULTS ICG was visible prior to incision in 44% of subjects. 99mTc identified a mean of 1.89 SLN per patient. ICG identified a mean of 1.87 SLN while methylene blue (MB) dye identified a mean of 0.71 SLN. 99mTc and ICG identified the same number of sentinel nodes per patient (P = .73) while methylene blue was inferior in its ability to localize sentinel nodes (P < .001). CONCLUSION Our findings indicate that ICG/fluorescence imaging has limited ability to identify the nodal basin preoperatively, but is equivalent to 99mTc for intraoperative identification of sentinel nodes and superior to MB.