Immune activation and response to pembrolizumab in POLE-mutant endometrial cancer

Mehnert, Janice M.; Panda, Anshuman; Zhong, Judy; Hirshfield, Kim M.; Damare, Sherri; Lane, Katherine; Sokol, Levi; Stein, Mark N.; Rodriguez-Rodriquez, Lorna; Kaufman, Howard L.; Ali, Siraj M.; Ross, Jeffrey S.; Pavlick, Dean C.; Bhanot, Gyan; White, Eileen; DiPaola, Robert S.; Lovell, Ann; Cheng, Jonathan D.; Ganesan, Shridar

doi:10.1172/jci84940

Cited by 335 publications

(258 citation statements)

References 23 publications

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“…Pembrolizumab has rarely been utilized in the gynecologic setting; however, it has been reported to have a favorable safety profile and durable antitumor activity in cervical and endometrial cancer [39][40][41] as well as gestational trophoblastic neoplasia [42]. Several toxicities have been encountered with pembrolizumab such as fatigue, nausea, myalgia, arthralgia, and colitis [31,35,37].…”

Section: Discussionmentioning

confidence: 99%

Pembrolizumab in Recurrent Squamous Cell Carcinoma of the Vulva: Case Report and Review of the Literature

Shields

Gordinier

2018

Gynecol Obstet Invest

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Advanced vulvar cancer is associated with a very poor prognosis. Surgical resection is the mainstay of treatment, with radiation indicated for areas at high risk for recurrence. When surgical and radiation options have been exhausted, the effectiveness of systemic chemotherapy is poor. No biologic or targeted agents have been approved for the management of advanced or recurrent vulvar cancer. Pembrolizumab, a humanized monoclonal antibody against programmed death 1 (PD-1), has been successfully used as a target of tumor immune therapy in small cell lung cancer and melanoma. We present the first case in the literature of a patient with recurrent vulvar cancer who was treated successfully with pembrolizumab. Caris next-generation testing revealed a PD-L1 and PD-1 mutation (PD-L1 positive, 2+, 100%). She attained a complete clinical remission after 2 cycles, and a CT scan after 6 cycles revealed a significant response by RECIST criteria. After completing 10 cycles, treatment was stopped due to complications of severe malnutrition related to narcotic abuse. A CT scan 10 weeks after the final treatment revealed no adenopathy. Pembrolizumab is a safe and effective chemotherapeutic agent to treat recurrent vulvar carcinoma.

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Section: Discussionmentioning

confidence: 99%

Pembrolizumab in Recurrent Squamous Cell Carcinoma of the Vulva: Case Report and Review of the Literature

Shields

Gordinier

2018

Gynecol Obstet Invest

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“…The finding in the last example complements correlative data demonstrating PD-L1 upregulation in enzalutamide-resistant prostate cancer cells (65), suggesting that the molecular features within the TME may evolve in response to treatment pressures, and hence by inference, sensitivity to immunotherapy may fluctuate at different stages of the disease process. Genomic factors such as possible underlying mismatch repair defects, defects in DNA proofreading due to loss of function of DNA polymerase epsilon (66) or BRCA2 mutations may have also influenced the antitumor activity seen in this subgroup and remain to be explored.…”

Section: Lessons Learned From Prior Immunotherapy Combinationsmentioning

confidence: 99%

From Famine to Feast: Developing Early-Phase Combination Immunotherapy Trials Wisely

Day

Monjazeb

Sharon

et al. 2017

Clinical Cancer Research

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Not until the turn of this century has immunotherapy become a fundamental component of cancer treatment. While monotherapy with immune modulators such as immune checkpoint inhibitors provides a subset of patients with durable clinical benefit and possible cure, combination therapy offers the potential for anti-tumor activity in a greater number of patients. The field of immunology has provided us with a plethora of potential molecules and pathways to target. This abundance makes it impractical to empirically test all possible combinations efficiently. We recommend that potential immunotherapy combinations be chosen based on sound rationale and available data to address the mechanisms of primary and acquired immune resistance. Novel trial designs may increase the proportion of patients receiving potentially efficacious treatments and, at the same time, better define the balance of clinical activity and safety. We believe that implementing a strategic approach in the early development of immunotherapy combinations will expedite the delivery of more effective therapies with improved safety and durable outcomes.

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“…Predictions linking tumor-infiltrating neutrophils and plasma cells to overall survival were validated by microscopy and IHC in lung adenocarcinoma [6]. Several groups have successfully applied CIBERSORT for cell deconvolution in various complex tissues, including microarray studies of peripheral blood [53], lung biopsies [54], triple negative breast cancers [55], and glioblastomas [56], and RNA-seq analyses of endometrial cancers [57]. …”

Section: Cell Deconvolution For Solid Tumorsmentioning

confidence: 99%

High-throughput genomic profiling of tumor-infiltrating leukocytes

Newman

Alizadeh

2016

Current Opinion in Immunology

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Tumors are complex ecosystems comprised of diverse cell types including malignant cells, mesenchymal cells, and tumor-infiltrating leukocytes (TILs). While TILs are well known to play important roles in many aspects of cancer biology, recent developments in immuno-oncology have spurred considerable interest in TILs, particularly in relation to their optimal engagement by emerging immunotherapies. Traditionally, the enumeration of TIL phenotypic diversity and composition in solid tumors has relied on resolving single cells by flow cytometry and immunohistochemical methods. However, advances in genome-wide technologies and computational methods are now allowing TILs to be profiled with increasingly high resolution and accuracy directly from RNA mixtures of bulk tumor samples. In this review, we highlight recent progress in the development of in silico tumor dissection methods, and illustrate examples of how these strategies can be applied to characterize TILs in human tumors to facilitate personalized cancer therapy.

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Immune activation and response to pembrolizumab in POLE-mutant endometrial cancer

Cited by 335 publications

References 23 publications

Pembrolizumab in Recurrent Squamous Cell Carcinoma of the Vulva: Case Report and Review of the Literature

Pembrolizumab in Recurrent Squamous Cell Carcinoma of the Vulva: Case Report and Review of the Literature

From Famine to Feast: Developing Early-Phase Combination Immunotherapy Trials Wisely

High-throughput genomic profiling of tumor-infiltrating leukocytes

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