Publications by authors named "Michael A Morse"

212 Publications

Changes in Peripheral Blood Regulatory T Cells and IL-6 and IL-10 Levels Predict Response of Pediatric Medulloblastoma and Germ Cell Tumors With Residual or Disseminated Disease to Craniospinal Irradiation.

Int J Radiat Oncol Biol Phys 2021 May 8. Epub 2021 May 8.

Department of Surgery, Duke University Medical Center, Durham, North Carolina. Electronic address:

Purpose: Radiation therapy (RT) modulates immune cells and cytokines, resulting in both clinically beneficial and detrimental effects. The changes in peripheral blood T lymphocyte subsets and cytokines during RT for pediatric brain tumors and the association of these changes with therapeutic outcomes have not been well described.

Methods And Materials: The study population consisted of children (n = 83, aged 3~18) with primary brain tumors (medulloblastoma, glioma, germ cell tumors (GCT), and central nervous system embryonal tumor-not otherwise specified), with or without residual or disseminated (R/D) diseases who were starting standard postoperative focal or craniospinal irradiation (CSI). Peripheral blood T lymphocyte subsets collected before and 4 weeks after RT were enumerated by flow cytometry. Plasma levels of interleukin (IL)-2, IL-4, IL-6, IL-10, tumor necrosis factor-α, interferon-γ, and IL-17A were measured by cytometric bead array.

Results: Patients with R/D lesions receiving CSI (n = 32) had a post-RT increase in the frequency of CD3+T and CD8+T cells, a decrease in CD4+T cells, and an increase in regulatory T cells (Tregs) and CD8+CD28- suppressor cells, which was more predominantly seen in these patients than in other groups. In the CSI group with such R/D lesions, consisting of patients with medulloblastoma and germ cell tumors, 19 experienced a complete response (CR) and 13 experienced a partial response (PR) on imaging at 4 weeks after RT. The post/pre-RT ratio of Tregs (P = .0493), IL-6 (P = .0111), and IL-10 (P = .0070) was lower in the CR group than in the PR group. Multivariate analysis revealed that the post/pre-RT ratios of Treg, IL-6, and IL-10 were independent predictors of CR (P < .0001, P = .018, P < .0001, respectively). The areas under the receiver operating curves and confidence intervals were 0.7652 (0.5831-0.8964), 0.7794 (0.5980-0.9067), and 0.7085 (0.5223-0.8552) for IL-6, IL-10, and Treg, respectively. The sensitivities of IL-6, IL-10, and Treg to predict radiotherapeutic responses were 100%, 92.3%, and 61.5%, and specificity was 52.6%, 57.9%, and 84.2%, respectively.

Conclusions: CSI treatment to those with R/D lesions predominantly exerted an effect on antitumor immune response compared with both R/D lesion-free but exposed to focal or CSI RT and with R/D lesions and exposed to focal RT. Such CSI with R/D lesions group experiencing CR is more likely to have a decrease in immunoinhibitory molecules and cells than patients who only achieve PR. Measuring peripheral blood Treg, IL-6, and IL-10 levels could be valuable for predicting radiotherapeutic responses of pediatric brain tumors with R/D lesions to CSI for medulloblastoma and intracranial germ cell tumors.
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http://dx.doi.org/10.1016/j.ijrobp.2021.04.041DOI Listing
May 2021

Serial assessment of circulating T lymphocyte phenotype and receptor repertoire during treatment of non-muscle invasive bladder cancer with adoptive T cell immunotherapy.

Am J Cancer Res 2021 15;11(4):1709-1718. Epub 2021 Apr 15.

Department of Surgery, Duke University Medical Center Durham, NC 27710, USA.

Recurrence and progression of non-muscle-invasive bladder cancer (NMIBC), frequent despite the availability of multiple treatment modalities, may be partly explained by the presence of immunosuppressive cell populations. We hypothesized that progression of disease could be prevented by the administration of an activated T cell immunotherapy (ACT) at time points when immunosuppressive populations increased in peripheral blood. In an N-of-1 study, a patient with multiple primary bladder high grade urothelial carcinomas, previously treated with standard local resection and chemotherapy but with evidence of progression, received ACT consisting of dendritic cells mixed with cytokine induced killer cells (DC/CIK), intravenously 18 times over a 6 year period at indicated time of observed increases in peripheral blood immunosuppressive CD8/CD28 cells. Peripheral blood was analyzed for T cell phenotype by flow cytometry, T cell receptor (TCR) repertoire, and circulating tumor DNA (ctDNA) by next generation sequencing (NGS) at the time of each infusion. Cystoscopy and pelvic CT scans were performed at routine intervals to assess clinical status of disease. There has been no recurrence or metastasis of urothelial carcinoma. Peripheral blood cytotoxic T cells and unique TCR clones increased and suppressive T cell populations decreased after DC/CIK infusions evidenced by the two more proof-of concept cases. ctDNA analysis detected mutations in six genes (ARID1B, MYCN, CDH23, SETD2, NOTCH4 and FAT1) which appeared at different times, but all of them disappeared after the DC-CIK infusions. These data suggest that DC/CIK infusions may be associated with beneficial changes in T cell phenotype, TCR repertoire, decreases in circulating tumor DNA and sustained recurrence-free survival.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085852PMC
April 2021

A case report of microsatellite instability (MSI)-high, amplified pancreatic adenocarcinoma with central nervous system metastasis.

AME Case Rep 2021 25;5:14. Epub 2021 Apr 25.

Duke Cancer Institute, Durham, NC, USA.

Pancreatic adenocarcinoma commonly presents as metastatic disease and harbors a dire prognosis due to its aggressive behavior, propensity for resistance to therapies, and lack of targetable driver mutations. Additionally, despite advances in other cancers, immunotherapy has been ineffective in this disease thus far and treatment remains centered around cytotoxic chemotherapy. Here, we present a case of a patient with pancreatic adenocarcinoma harboring both high microsatellite instability (MSI-H) and amplification. After an initial response to standard-of-care chemotherapy with FOLFIRINOX followed by progression, she was treated with dual immune checkpoint blockade, which resulted in a period of disease control. This was complicated by the development of autoimmune hypophysitis and an incidental finding of brain metastasis on magnetic resonance imaging (MRI). Her extracranial disease progressed while receiving stereotactic radiosurgery, with findings of lymphangitic spread in her lungs, and her treatment was changed to gemcitabine/nab-paclitaxel with trastuzumab. This resulted in a degree of extracranial disease control, though she experienced progressive brain metastases despite radiation and therapeutic switch to lapatinib and trastuzumab. Ultimately, the patient developed leptomeningeal disease which was not controlled by intrathecal trastuzumab. Given the rarity of central nervous system metastasis, amplification, and MSI in pancreatic cancer, this patient's presentation represents a confluence of multiple unique features. This case highlights the clinical value of up-front next-generation sequencing in metastatic pancreatic cancer and the ability of pancreatic cancer with actionable molecular variants to develop atypical sites of disease and adaptive resistance.
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http://dx.doi.org/10.21037/acr-20-154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060150PMC
April 2021

Vaccine Therapies for Cancer: Then and Now.

Target Oncol 2021 03 29;16(2):121-152. Epub 2021 Jan 29.

Lillian S. Wells Department of Neurosurgery, Preston A. Wells Jr. Center for Brain Tumor Therapy, UF Clinical and Translational Science Institute, University of Florida, Gainesville, FL, USA.

There are strong biologic and preclinical rationales for the development of therapeutic cancer vaccines; however, the clinical translation of this treatment strategy has been challenging. It is now understood that many previous clinical trials of cancer vaccines used target antigens or vaccine designs that inherently lacked sufficient immunogenicity to induce clinical responses. Despite the historical track record, breakthrough advances in cancer immunobiology and vaccine technologies have supported continued interest in therapeutic cancer vaccinations, with the hope that next-generation vaccine strategies will enable patients with cancer to develop long-lasting anti-tumor immunity. There has been substantial progress identifying antigens and vaccine vectors that lead to strong and broad T cell responses, tailoring vaccine designs to achieve optimal antigen presentation, and finding combination partners employing complementary mechanisms of action (e.g., checkpoint inhibitors) to overcome the diverse methods cancer cells use to evade and suppress the immune system. Results from randomized, phase 3 studies testing therapeutic cancer vaccines based on these advances are eagerly awaited. Here, we summarize the successes and failures in the clinical development of cancer vaccines, address how this historical experience and advances in science and technology have shaped efforts to improve vaccines, and offer a clinical perspective on the future role of vaccine therapies for cancer.
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http://dx.doi.org/10.1007/s11523-020-00788-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845582PMC
March 2021

Cabozantinib and Panitumumab for RAS Wild-Type Metastatic Colorectal Cancer.

Oncologist 2021 Jun 9;26(6):465-e917. Epub 2021 Feb 9.

Duke University Medical Center, Durham, North Carolina, USA.

Lessons Learned: Antitumor activity was observed in the study population. Dose modifications of cabozantinib improve long-term tolerability. Biomarkers are needed to identify patient populations most likely to benefit. Further study of cabozantinib with or without panitumumab in patients with metastatic colorectal cancer is warranted.

Background: The epidermal growth factor receptor (EGFR) antibody panitumumab is active in patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC), but nearly all patients experience resistance. MET amplification is a driver of panitumumab resistance. Cabozantinib is an inhibitor of multiple kinases, including vascular endothelial growth factor receptor 2 (VEGFR2) and c-MET, and may delay or reverse anti-EGFR resistance.

Methods: In this phase Ib clinical trial, we established the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of cabozantinib and panitumumab. We then treated an expansion cohort to further describe the tolerability and clinical activity of the RP2D. Eligibility included patients with KRAS WT mCRC (later amended to include only RAS WT mCRC) who had received prior treatment with a fluoropyrimidine, oxaliplatin, irinotecan, and bevacizumab.

Results: Twenty-five patients were enrolled and treated. The MTD/RP2D was cabozantinib 60 mg p.o. daily and panitumumab 6 mg/kg I.V. every 2 weeks. The objective response rate (ORR) was 16%. Median progression free survival (PFS) was 3.7 months (90% confidence interval [CI], 2.3-7.1). Median overall survival (OS) was 12.1 months (90% CI, 7.5-14.3). Five patients (20%) discontinued treatment due to toxicity, and 18 patients (72%) required a dose reduction of cabozantinib.

Conclusion: The combination of cabozantinib and panitumumab has activity. Dose reductions of cabozantinib improve tolerability.
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http://dx.doi.org/10.1002/onco.13678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176979PMC
June 2021

Infiltration of metastatic lymph nodes with PD-1 T cells is associated with improved disease-free and overall survival in resected N NSCLC.

Am J Cancer Res 2020 1;10(12):4435-4449. Epub 2020 Dec 1.

Department of Surgery, Duke University Medical Center Durham, NC 27710, USA.

Tumor metastases to regional lymph nodes are associated with worse outcome for patients with resected non-small cell lung cancer (NSCLC), but there is a wide variation in survival. We hypothesized that infiltration of tumor-involved lymph nodes with activated effector T cells would impact subsequent outcome. A total of 54 lymph nodes (27 N and 15 N collected from 12 patients with Stage IIB (TNM) and 12 N lymph nodes collected from 10 patients with Stage IIA (TNM) who underwent lymphadenectomy during surgical management of their NSCLC) were analyzed for effector T cells expressing activation markers PD-1 and TIM-3 using the -multiple immunofluorescence assay. The frequency of CD3CD8 (P=0.0001), CD3CD8TIM-3 (P<0.0001), and CD3CD8TIM-3Ki-67 (P<0.0001) T cells was greater in lymph nodes of IIA patients compared with IIB patients; however the frequency of CD3CD8PD-1 (P=0.0086), CD3CD8TIM-3 (P=0.0129), CD3CD8PD-1Ki-67 (P<0.0001) and CD3CD8TIM-3Ki-67 (P=0.0001) T cells was greater among the tumor involved (N) nodes of N1 patients compared with the tumor-uninvolved (N) nodes. The frequency of intranodal CD3CD8, CD3CD8PD-1 and CD3CD8PD-1Ki-67 T cells in N nodes was associated with prolonged progression-free (PFS) and overall survival (OS). These data suggest that CD3CD8TIM-3 T cells may suppress tumor spread to regional lymph nodes but once tumor cells metastasize to lymph nodes, CD3/CD8/PD-1/Ki67 T cells localizing to N nodes may prevent further tumor spread, resulting in prolonged survival.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783752PMC
December 2020

Long-term survival of patients with stage III colon cancer treated with VRP-CEA(6D), an alphavirus vector that increases the CD8+ effector memory T cell to Treg ratio.

J Immunother Cancer 2020 11;8(2)

Surgery, Duke University School of Medicine, Durham, North Carolina, USA

Background: There remains a significant need to eliminate the risk of recurrence of resected cancers. Cancer vaccines are well tolerated and activate tumor-specific immune effectors and lead to long-term survival in some patients. We hypothesized that vaccination with alphaviral replicon particles encoding tumor associated antigens would generate clinically significant antitumor immunity to enable prolonged overall survival (OS) in patients with both metastatic and resected cancer.

Methods: OS was monitored for patients with stage IV cancer treated in a phase I study of virus-like replicon particle (VRP)-carcinoembryonic antigen (CEA), an alphaviral replicon particle encoding a modified CEA. An expansion cohort of patients (n=12) with resected stage III colorectal cancer who had completed their standard postoperative adjuvant chemotherapy was administered VRP-CEA every 3 weeks for a total of 4 immunizations. OS and relapse-free survival (RFS) were determined, as well as preimmunization and postimmunization cellular and humoral immunity.

Results: Among the patients with stage IV cancer, median follow-up was 10.9 years and 5-year survival was 17%, (95% CI 6% to 33%). Among the patients with stage III cancer, the 5-year RFS was 75%, (95%CI 40% to 91%); no deaths were observed. At a median follow-up of 5.8 years (range: 3.9-7.0 years) all patients were still alive. All patients demonstrated CEA-specific humoral immunity. Patients with stage III cancer had an increase in CD8 +T (in 10/12) and decrease in FOXP3 +Tregs (in 10/12) following vaccination. Further, CEA-specific, IFNγ-producing CD8+granzyme B+T cells were increased.

Conclusions: VRP-CEA induces antigen-specific effector T cells while decreasing Tregs, suggesting favorable immune modulation. Long-term survivors were identified in both cohorts, suggesting the OS may be prolonged.
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http://dx.doi.org/10.1136/jitc-2020-001662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7661359PMC
November 2020

Survival and Clinical Outcomes with Telotristat Ethyl in Patients with Carcinoid Syndrome.

Cancer Manag Res 2020 7;12:9713-9719. Epub 2020 Oct 7.

Duke Cancer Institute, School of Medicine, Duke University, Durham, NC 27710, USA.

Purpose: The TELEACE study showed reductions in tumor size in patients with neuroendocrine tumors, receiving telotristat ethyl in US clinical practice. Here, we report progression-free survival, time to tumor progression, changes in carcinoid syndrome symptoms, and indictors of overall health.

Patients And Methods: This was a retrospective, single arm, pre-post medical chart review of patients with locally advanced or metastatic neuroendocrine tumors and documented carcinoid syndrome receiving telotristat ethyl for at least 6 months. Patients with poorly differentiated tumors, mixed tumor types or conflicting clinical trial enrollment were excluded. Descriptive statistics, Kaplan-Meier and chi-square tests were used to evaluate PFS, tumor progression, changes in symptoms, body weight and ECOG performance status before and after telotristat ethyl initiation. Subgroup analyses were conducted in patients with the same pre- and post-telotristat ethyl background treatment.

Results: Anonymized data for 200 patients were provided by 114 physicians; patients received telotristat ethyl for a median of 9 months. Median time to tumor progression was 39.8 months (IQR, 18.7-39.8); most had no tumor progression at 6 (92%) and 12 months (87%). Median progression-free survival was 23.7 months (17.8-39.8); most had progression-free survival at 6 (90%) and 12 months (80%). Results were consistent in the subgroup of 65 patients with the same pre/post background treatment. Nearly all patients had improved carcinoid syndrome symptoms, stable or improved weight and ECOG performance status.

Conclusion: Patients showed improvements in clinical outcomes and indicators of overall health following treatment with telotristat ethyl in this exploratory pilot study, consistent with previously observed reductions in tumor size.
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http://dx.doi.org/10.2147/CMAR.S276519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7548219PMC
October 2020

Differential Diagnosis of Diarrhea in Patients With Neuroendocrine Tumors.

Pancreas 2020 10;49(9):1123-1130

Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Patients with neuroendocrine tumors (NETs) and carcinoid syndrome experience diarrhea that can have a debilitating effect on quality of life. Diarrhea also may develop in response to other hormonal syndromes associated with NETs, surgical complications, medical comorbidities, medications, or food sensitivities. Limited guidance on the practical approach to the differential diagnosis of diarrhea in these patients can lead to delays in appropriate treatment. This clinical review and commentary underscore the complexity in identifying the etiology of diarrhea in patients with NETs. Based on our collective experience and expertise, we offer a practical algorithm to guide medical oncologists and other care providers to expedite effective management of diarrhea and related symptoms in patients with NETs.
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http://dx.doi.org/10.1097/MPA.0000000000001658DOI Listing
October 2020

Antiproliferative Effects of Telotristat Ethyl in Patients with Neuroendocrine Tumors: The TELEACE Real-World Chart Review Study.

Cancer Manag Res 2020 30;12:6607-6614. Epub 2020 Jul 30.

Neuroendocrine Tumor Program at Penn Medicine, Philadelphia, PA, USA.

Purpose: Neuroendocrine tumors (NETs) associated with carcinoid syndrome (CS) overproduce serotonin, mediated by tryptophan hydroxylase-1 (TPH1). The TPH inhibitor telotristat ethyl (TE) reduces peripheral serotonin and relieves CS symptoms. We conducted a real-world clinical practice study to explore the effects of TE on tumor growth in patients with NETs and CS.

Patients And Methods: Single-arm, pre/post chart review study of patients with advanced NETs who received TE for ≥6 months and had ≥2 radiological scans within 12 months before and ≥1 scan after TE initiation. Linear regression and longitudinal analyses assessed changes in tumor size controlling for background NET treatment.

Results: Two hundred patients were enrolled, most (61%) had well-differentiated gastrointestinal NETs (61%) and received TE for an average of 12 months (SD, 7.3). Mean reduction in tumor size after TE initiation was 0.59 cm (p=0.006). Longitudinal analysis showed an 8.5% reduction in tumor size (p=0.045) from pre- to post-TE periods. Documented NET treatment prior to initiating TE and time between scans were not significant predictors of changes in tumor size. Results were consistent in a subgroup of patients with the same documented NET treatment before and after initiating TE.

Conclusion: TE may have antitumor effects consistent with serotonin overproduction in tumor growth.
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http://dx.doi.org/10.2147/CMAR.S261257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402667PMC
July 2020

Clinical efficacy of intra-cavitary infusions of autologous dendritic cell/cytokine-induced killer cell products for the treatment of refractory malignant pleural effusions and ascites.

Am J Transl Res 2020 15;12(7):3940-3952. Epub 2020 Jul 15.

Department of Surgery, Duke University Medical Center Durham, NC 27710, USA.

To explore the safety and efficacy of intra-cavitary infusions of autologous mixed dendritic cell (DC)-cytokine-induced killer (CIK) cell products in advanced cancer patients with malignant pleural effusions or ascites. DC-CIKs were expanded ex vivo (mean yield of 1.36×10 cells (range, 0.74~4.98×10)) from peripheral blood mononuclear cells obtained by repeated venipuncture or apheresis. Patients received at least 1 cycle of 3 infusions of the DC-CIKs administered by indwelling catheter into the pleural or peritoneal cavity every other day. The volume of malignant effusions was assessed radiologically. Peripheral blood lymphocyte populations were enumerated by flow cytometry. Quality of life (QoL) during the DC-CIK infusions was assessed by the EORTC QLQ-30 instrument. ctDNA sequencing was performed to analyze gene clonal load and molecular tumor burden during the infusion treatment. Thirty-seven patients with breast, lung and other malignancies were enrolled. The results showed that intra-cavitary DC-CIK infusions (16 intrapleural and 21 intraperitoneal) were well-tolerated with no grade 3/4 adverse events. There was one complete response with effusion disappearance (CR) (3%), 13 partial responses (PR) (35%), 12 with stable disease (SD) (32%) and 11 with progressive disease (PD) (30%), resulting in a clinical effusion control rate (CCR) of 70% (26/37). The total number of infused CIKs and the CD3+/CD8+ and CD8+/CD28+ T cell frequencies within the CIKs were associated with effusion control (P=0.013). Moreover, increased peripheral blood CD3+/CD8+ (P=0.035) and decreased CD4+/CD25+ T cell frequencies (P=0.041) following the DC-CIK infusions were associated with malignant effusion and ascites control. Reductions in ctDNA correlated with clinical benefit. In conclusion, intra-cavitary autologous cellular immunotherapy is an alternative method to effectively control malignant pleural effusions and ascites. The overall effusion control rate was associated with higher peripheral blood effector T cell frequencies.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407744PMC
July 2020

Stimulation of Oncogene-Specific Tumor-Infiltrating T Cells through Combined Vaccine and αPD-1 Enable Sustained Antitumor Responses against Established HER2 Breast Cancer.

Clin Cancer Res 2020 09 30;26(17):4670-4681. Epub 2020 Jul 30.

Department of Surgery, Division of Surgical Sciences, Duke University, Durham North Carolina.

Purpose: Despite promising advances in breast cancer immunotherapy, augmenting T-cell infiltration has remained a significant challenge. Although neither individual vaccines nor immune checkpoint blockade (ICB) have had broad success as monotherapies, we hypothesized that targeted vaccination against an oncogenic driver in combination with ICB could direct and enable antitumor immunity in advanced cancers.

Experimental Design: Our models of HER2 breast cancer exhibit molecular signatures that are reflective of advanced human HER2 breast cancer, with a small numbers of neoepitopes and elevated immunosuppressive markers. Using these, we vaccinated against the oncogenic HER2Δ16 isoform, a nondriver tumor-associated gene (GFP), and specific neoepitopes. We further tested the effect of vaccination or anti-PD-1, alone and in combination.

Results: We found that only vaccination targeting HER2Δ16, a driver of oncogenicity and HER2-therapeutic resistance, could elicit significant antitumor responses, while vaccines targeting a nondriver tumor-specific antigen or tumor neoepitopes did not. Vaccine-induced HER2-specific CD8 T cells were essential for responses, which were more effective early in tumor development. Long-term tumor control of advanced cancers occurred only when HER2Δ16 vaccination was combined with αPD-1. Single-cell RNA sequencing of tumor-infiltrating T cells revealed that while vaccination expanded CD8 T cells, only the combination of vaccine with αPD-1 induced functional gene expression signatures in those CD8 T cells. Furthermore, we show that expanded clones are HER2-reactive, conclusively demonstrating the efficacy of this vaccination strategy in targeting HER2.

Conclusions: Combining oncogenic driver targeted vaccines with selective ICB offers a rational paradigm for precision immunotherapy, which we are clinically evaluating in a phase II trial (NCT03632941).
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http://dx.doi.org/10.1158/1078-0432.CCR-20-0389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483405PMC
September 2020

Heat shock protein 90-targeted photodynamic therapy enables treatment of subcutaneous and visceral tumors.

Commun Biol 2020 05 8;3(1):226. Epub 2020 May 8.

Department of Surgery, Duke University Medical Center, Durham, NC, 27710, USA.

Photodynamic therapy (PDT) ablates malignancies by applying focused near-infrared (nIR) light onto a lesion of interest after systemic administration of a photosensitizer (PS); however, the accumulation of existing PS is not tumor-exclusive. We developed a tumor-localizing strategy for PDT, exploiting the high expression of heat shock protein 90 (Hsp90) in cancer cells to retain high concentrations of PS by tethering a small molecule Hsp90 inhibitor to a PS (verteporfin, VP) to create an Hsp90-targeted PS (HS201). HS201 accumulates to a greater extent than VP in breast cancer cells both in vitro and in vivo, resulting in increased treatment efficacy of HS201-PDT in various human breast cancer xenografts regardless of molecular and clinical subtypes. The therapeutic index achieved with Hsp90-targeted PDT would permit treatment not only of localized tumors, but also more diffusely infiltrating processes such as inflammatory breast cancer.
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http://dx.doi.org/10.1038/s42003-020-0956-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210113PMC
May 2020

Phase II Study of Ensituximab, a Novel Chimeric Monoclonal Antibody, in Adults with Unresectable, Metastatic Colorectal Cancer.

Clin Cancer Res 2020 07 17;26(14):3557-3564. Epub 2020 Apr 17.

Department of Oncology, University of Texas Southwestern Medical Center of Dallas, Dallas, Texas.

Purpose: Patients with metastatic colorectal cancer refractory to chemotherapy have limited treatment options. Ensituximab (NEO-102) is a novel chimeric mAb targeting a variant of with specificity to colorectal cancer.

Patients And Methods: Single-arm, phase II trial assessed the efficacy and safety of ensituximab in patients with advanced, refractory cancer who expressed antigen in tumor tissue. Ensituximab was administered intravenously every 2 weeks with 3 mg/kg as recommended phase II dose (RP2D). A minimum sample size of 43 patients was required on the basis of the assumption that ensituximab would improve median overall survival (OS) by 7 months using a one-sided significance level of 10% and 80% power. Written informed consent was obtained from all patients.

Results: Sixty-three patients with advanced, refractory colorectal cancer were enrolled and 53 subjects were treated in phase II arm. Median age was 58 years and 46% of the patients were female. Among 57 evaluable patients, median OS was 6.8 months. No responses were observed, and stable disease was achieved in 21% of the patients. The most common treatment-related adverse events (AE) at RP2D included fatigue (38%), anemia (30%), nausea (15%), vomiting (11%), increased bilirubin (9%), constipation (8%), decreased appetite (6%), and diarrhea (6%). Serious AEs at least possibly related to ensituximab occurred in 4 patients and included anemia, nausea, increased bilirubin, and hypoxia. No patients discontinued treatment due to drug-related AEs.

Conclusions: Ensituximab was well tolerated and demonstrated modest antitumor activity in patients with heavily pretreated refractory colorectal cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-0426DOI Listing
July 2020

DC-CIK as a widely applicable cancer immunotherapy.

Expert Opin Biol Ther 2020 06 13;20(6):601-607. Epub 2020 Feb 13.

Department of Medical Oncology, Beijing Key Laboratory for Therapeutic Cancer Vaccines, Capital Medical University Cancer Center, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.

: Immunotherapy is now a standard treatment for many malignancies. Although immune checkpoint inhibition has demonstrated substantial efficacy by enhancing T cell activation and function in the tumor microenvironment, adoptive transfer of T and NK cell products promises to provide activated cells capable of immediate and direct tumor destruction. A widely applicable, non-MHC dependent, cellular therapy, consisting of generated dendritic cells (DC) combined with cytokine-induced killer cells (CIK), is highly efficient to produce from individual patients and has demonstrated safety and efficacy alone or with chemotherapy.: We summarize the clinical data from studies of DC-CIK and discuss future research directions.: Patients with a wide variety of tumor types who have received DC-CIK therapy may experience clinical responses. This versatile therapy synergizes with other anti-cancer therapies including chemotherapy and immunotherapy.
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http://dx.doi.org/10.1080/14712598.2020.1728250DOI Listing
June 2020

Immune correlates of clinical benefit in a phase I study of hyperthermia with adoptive T cell immunotherapy in patients with solid tumors.

Int J Hyperthermia 2019 11;36(sup1):74-82

Department of Surgery, Duke University Medical Center, Durham, NC, USA.

To characterize the T cell receptor (TCR) repertoire, serum cytokine levels, peripheral blood T lymphocyte populations, safety, and clinical efficacy of hyperthermia (HT) combined with autologous adoptive cell therapy (ACT) and either salvage chemotherapy (CT) or anti-PD-1 antibody in patients with previously treated advanced solid tumors. Thirty-three (33) patients with ovarian, pancreatic, gastric, colorectal, cervical, or endometrial cancer were recruited into the following therapeutic groups: HT + ACT ( = 10), HT + ACT + anti-PD-1 inhibitor (pembrolizumab) ( = 11) and HT + ACT + CT ( = 12). Peripheral blood was collected to analyze TCR repertoire, measurements of cytokines levels and lymphocyte sub-populations before and after treatment. The objective response rate (ORR) was 30% (10/33), including three complete responses (CR) (9.1%) and seven partial responses (PR) (21.2%) and a disease control rate (DCR = CR + PR + SD) of 66.7% (22 of 33). The most common adverse reactions, blistering, subcutaneous fat induration, local heat-related pain, vomiting and sinus tachycardia, were observed in association with HT. IL-2, IL-4, TNF-α, and IFN-γ levels in peripheral blood were significantly increased among the clinical responders ( < 0.05) while IL-6 and IL-10 were elevated among those with progressive disease ( < 0.05). Peripheral blood CD8/CD28 T cells increased ( = 0.002), while the CD4/CD25/CD127Treg cells decreased after therapy ( = 0.012). TCR diversity was substantially increased among the clinical responders. Combining HT with ACT plus either CT or anti-PD-1 antibody was safe, generated clinical responses in previously treated advanced cancers, and promoted TCR repertoire diversity and favorable changes in serum IL-2, IL-4, TNF-α, and IFN-γ levels in clinical responders.
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http://dx.doi.org/10.1080/02656736.2019.1647350DOI Listing
November 2019

Predictive significance of T cell subset changes during generation of adoptive cellular therapy products for the treatment of advanced non-small cell lung cancer.

Oncol Lett 2019 Dec 4;18(6):5717-5724. Epub 2019 Oct 4.

Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.

Adoptive T cell immunotherapy with cytokine-induced killer cells (CIKs) has been demonstrated to prolong the survival of patients with advanced non-small cell lung cancer (NSCLC). The aim of the present study was to evaluate whether the expansion of effector T cells and the decrease of regulatory T cells (Tregs) that occurred during the generation of DC-CIKs were associated with improved clinical outcome in patients who received treatment. CIKs were generated over a 28-day period from the peripheral blood apheresis product of 163 patients with advanced cancer (including 30 with NSCLC). CIKs were also generated from an additional cohort of 65 patients with NSCLC over a 15-day period. The progression-free survival (PFS) and overall survival (OS) time of patients treated with CIKs was determined by reviewing the patients' medical records. The number of CIKs gradually increased during the culture period and peaked at day 15, followed by a slight decline until day 28. Similarly, the percentages of T cell subtypes associated with anti-tumor activity (CD3, CD3CD4, CD3CD8 and CD8CD28) peaked at day 15. Although the percentage of CD4CD25CD127 Tregs increased by day 7, a decrease was subsequently observed. Among the 95 patients with NSCLC, those with a post/pre-culture ratio of CD8CD28 T lymphocytes >2.2 had significantly better PFS and OS compared with those with ratios ≤2.2. Those with a post/pre-culture CD4CD25CD127 Treg ratio ≤0.6 had significantly better OS and PFS compared with those with ratios >0.6. The peak expansion of CIKs from peripheral blood mononuclear cells occurred at day 15 of culture. PFS and OS were associated with post/pre-culture CD8CD28 T lymphocyte ratio >2.2 and post/pre-culture CD4CD25CD127 Treg ratio <0.6 in the CIKs of patients with advanced NSCLC treated with adoptive T cell immunotherapy. Further efforts are underway to optimize the DC-CIK infusion for cancer immunotherapy.
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http://dx.doi.org/10.3892/ol.2019.10964DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6865835PMC
December 2019

A phase Ib study of capecitabine and ziv-aflibercept followed by a phase II single-arm expansion cohort in chemotherapy refractory metastatic colorectal cancer.

BMC Cancer 2019 Nov 1;19(1):1032. Epub 2019 Nov 1.

Genentech, Inc., South San Francisco, CA, 94080, USA.

Background: Patients with chemotherapy refractory metastatic colorectal cancer (CRC) have a poor prognosis and limited therapeutic options. In this phase Ib/II clinical trial, we established the maximum tolerated dose (MTD) and recommended phase II dose (RPTD) for the combination of capecitabine and ziv-aflibercept, and then we evaluated the efficacy of the combination in patients with chemotherapy refractory metastatic CRC.

Methods: All patients were required to have a Karnofsky Performance Status > 70% and adequate organ function. The phase Ib dose escalation cohort included patients with advanced solid tumors who had progressed on all standard therapies. Using a standard 3 + 3 design, we identified the MTD and RPTD for the combination. Fifty patients with metastatic CRC who had progressed on or were intolerant of a fluoropyrimidine, oxaliplatin, irinotecan, and bevacizumab were then enrolled in a single-arm phase II expansion cohort, and were treated at the RPTD. Prior EGFR antibody therapy was required for subjects with RAS wildtype tumors. The primary endpoint for the expansion cohort was progression-free survival (PFS) at two months. Secondary endpoints included objective response rate (ORR) and overall survival (OS).

Results: A total of 63 patients were enrolled and evaluable for toxicity (13 dose escalation; 50 expansion). The MTD and RPTD were: capecitabine 850 mg/m2, P.O. bid, days 1-14, and ziv-aflibercept 6 mg/kg I.V., day 1, of each 21-day cycle. In the expansion cohort, 72% of patients were progression-free at two months (95% confidence interval [CI], 60-84%). Median PFS and OS were 3.9 months (95% CI, 2.3-4.5) and 7.1 months (95% CI: 5.8-10.0), respectively. Among all patients evaluable for toxicity, the most common treatment related adverse events (all grade [%]; grade ≥ 3 [%]) included palmar-plantar erythrodysesthesia (41%; 6%), hypertension (33%; 22%), and mucositis (19%; 5%). RNA was isolated from archived tumor specimens and gene expression analyses revealed no association between angiogenic biomarkers and clinical outcomes.

Conclusion: The combination of capecitabine and ziv-aflibercept at the RPTD demonstrated acceptable safety and tolerability. PFS at 2 months in patients with chemotherapy refractory metastatic CRC was significantly greater than that in historical controls, indicating that this combination warrants further study.

Trial Registration: This clinical trial was registered in the www.clinicaltrials.gov system as NCT01661972 on July 31, 2012.
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http://dx.doi.org/10.1186/s12885-019-6234-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824108PMC
November 2019

Long-Term Outcomes of 125 Patients With Metastatic Pheochromocytoma or Paraganglioma Treated With 131-I MIBG.

J Clin Endocrinol Metab 2020 03;105(3)

Department of Medicine, Division of Hematology and Oncology, Duke University Medical Center, Durham, North Carolina.

Context: Prognosis of metastatic pheochromocytoma/paraganglioma following 131-Iodine metaiodobenzylguanidine (MIBG) is incompletely characterized due to small samples and shorter follow-up in these rare, often indolent tumors.

Objective: To describe long-term survival, frequency, and prognostic impact of imaging, biochemical, and symptomatic response to 131-I MIBG.

Design: Retrospective chart and imaging review at a tertiary referral center.

Patients: Six hundred sixty-eight person-years of follow-up in 125 patients with metastatic pheochromocytoma/paraganglioma with progression through prior multimodal treatment.

Intervention: Median 18 800 MBq 131-I MIBG.

Main Outcome Measures: Overall survival, Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST) imaging response, symptomatic response per chart review, and biochemical response (20% change over 2 consecutive assays of catecholamines, vanillylmandelic acid, metanephrines, or chromogranin A).

Results: Median survival standard deviation [SD] from diagnosis was 11.5 years [2.4]; following metastasis, 6.5 years [0.8]; post treatment, 4.3 years [0.7]. Among 88 participants with follow-up imaging, 1% experienced complete response, 33% partial response, 53% stability, and 13% progression. Fifty-one percent showed subsequent progression, median progression-free survival [SD] of 2.0 years [0.6]. Stability/response vs progression at first imaging follow-up (3-6 months) predicted improved survival, 6.3 vs 2.4 years (P = 0.021). Fifty-nine percent of 54 patients demonstrated biochemical response. Fifty percent of these relapsed, with median time to laboratory progression [SD] of 2.8 years [0.7]. Biochemical response did not predict extended survival. Seventy-five percent of 83 patients reported improvement in pretreatment symptoms, consisting primarily of pain (42%), fatigue (27%), and hypertension (14%). Sixty-one percent of these patients experienced subsequent symptomatic progression at median [SD] 1.8 years [0.4]. Symptomatic response did not predict extended survival.

Conclusions: Imaging, symptomatic, and laboratory response to multimodal treatment including high-dose 131-I MIBG were achieved on long-term follow-up in metastatic pheochromocytoma or paraganglioma. Imaging response at 3 to 6 months was prognostic.
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http://dx.doi.org/10.1210/clinem/dgz074DOI Listing
March 2020

Adoptive immunotherapy with autologous T-cell infusions reduces opioid requirements in advanced cancer patients.

Pain 2020 01;161(1):127-134

Department of Surgery, Duke University Medical Center, Durham, United States.

Relief of cancer-related pain remains challenging despite the availability of a range of opioid and nonopioid medications. Animal models demonstrate that T lymphocytes may mediate analgesia by producing endogenous opioids, but definitive clinical data are limited. Transfer of ex vivo adoptive cellular therapy (ACT) is being tested as an anticancer therapy. We retrospectively reviewed the medical charts of 357 patients with various malignancies who received 3 intravenous infusions of autologous cytokine-activated T-cell-enriched products. Among these were 55 patients who required opioids for moderate or severe cancer-related pain. Opioid dosage and cancer pain score were recorded daily for 2 consecutive weeks before and 2 weeks after the ACT infusions. The average oral morphine equivalent doses and cancer pain scores were significantly decreased after the ACT infusions. The proportion of patients with breakthrough pain also declined. Moreover, higher frequencies of expanded CD3, CD3/CD4, and CD3/CD8 T cells within the ACT product were associated with favorable analgesic effects. Transient elevations in CD3 and CD3/CD8T-cell subpopulations and decreases in CD4CD25 Treg were observed in patients' blood after the ACT. In conclusion, ACT was capable of reducing cancer pain severity and opioid consumption and favorably modulating peripheral blood T-cell populations.
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http://dx.doi.org/10.1097/j.pain.0000000000001702DOI Listing
January 2020

Molecular profiling of biliary cancers reveals distinct molecular alterations and potential therapeutic targets.

J Gastrointest Oncol 2019 Aug;10(4):652-662

Division of Medical Oncology, Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA.

Background: Biliary tract cancers (BTCs) are a heterogeneous group of aggressive, rare malignancies with limited standard chemotherapeutic options for advanced disease. Recent studies have demonstrated potential novel biliary cancer targets and a possible role for immunotherapy in the treatment of patients with this disease. Intrahepatic cholangiocarcinoma (IHCC), extrahepatic cholangiocarcinoma (EHCC), and gallbladder carcinoma (GBC) are frequently grouped together in clinical trials despite differences in tumor biology.

Methods: To further investigate tumor biology differences, we profiled 1,502 BTCs using next-generation sequencing (NGS), immunohistochemistry, hybridization, and RNA sequencing.

Results: IHCCs had higher rates of , , and mutations and fusions; had higher rates of , , and mutations; and GBCs had higher rates of homologous recombination repair deficiency and Her2/neu overexpression and amplification. IHCCs and GBCs had higher rates of potential positive predictive biomarkers for immune checkpoint inhibition (PD-L1 expression, high microsatellite instability, and high tumor mutational burden) than EHCCs.

Conclusions: These findings support clinical molecular profiling of BTCs to inform potential therapeutic selection and clinical trial design based on the primary tumor's site of origin within the biliary tree.
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http://dx.doi.org/10.21037/jgo.2018.08.18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6657312PMC
August 2019

Perspectives on Treatment of Metastatic Colorectal Cancer with Immune Checkpoint Inhibitor Therapy.

Oncologist 2020 01 5;25(1):33-45. Epub 2019 Aug 5.

Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois, USA.

Despite lengthening survival, death rates from metastatic colorectal cancer (CRC) remain unacceptably high, with a bright spot being the demonstration of durable responses in patients with CRC who have mismatch repair-deficient (dMMR) and/or microsatellite instability-high (MSI-H) tumors and are treated with immune checkpoint inhibitor therapy. Nivolumab and pembrolizumab, as well as nivolumab in combination with low-dose ipilimumab-all checkpoint inhibitors-are currently approved by the U.S. Food and Drug Administration (FDA) for patients with MSI-H/dMMR metastatic CRC that progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. Nonetheless, there are a number of questions and considerations in the use of these checkpoint inhibitor therapies. Using a question-and-answer format, this review summarizes the scientific rationale for immune checkpoint inhibitor therapy in CRC, including the effects of tumor factors such as genetic aberrations and mutational load on the immune response, particularly in patients with MSI-H/dMMR disease. We discuss response patterns, response criteria, and immune-related adverse events using findings from published efficacy and safety data of immune checkpoint inhibitor therapy in metastatic CRC. We also discuss issues surrounding treatment sequencing, incorporating approved checkpoint inhibitors into the current treatment paradigm, and the multiple investigational strategies that may optimize immunotherapy for advanced CRC in the future, including novel combination therapies. IMPLICATIONS FOR PRACTICE: Colorectal cancer (CRC) is the third most common cancer in the U.S. Despite advances in chemotherapy, survival remains poor for patients with metastatic CRC. Certain immunotherapy agents have demonstrated long-lasting responses in previously treated patients with immune-responsive microsatellite instability-high/mismatch repair-deficient metastatic CRC, leading to U.S. Food and Drug Administration approval of the immune checkpoint inhibitors nivolumab (with or without low-dose ipilimumab) and pembrolizumab in this population. Combination therapy (e.g., nivolumab with low-dose ipilimumab) has demonstrated numerically higher response rates and improved long-term clinical benefit relative to anti-programmed death-1 monotherapy. Ongoing trials are evaluating immunotherapy in the broader CRC population and novel combinations to optimize immunotherapy for advanced CRC.
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http://dx.doi.org/10.1634/theoncologist.2019-0176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6964145PMC
January 2020

Impact of synchronized anti-PD-1 with Ad-CEA vaccination on inhibition of colon cancer growth.

Immunotherapy 2019 08 13;11(11):953-966. Epub 2019 Jun 13.

Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.

The purpose of this study was to determine whether addition of anti-PD-1 antibody increased the immunogenicity and anti-tumor activity of Ad-CEA vaccination in a murine model of colon cancer. Ad-CEA was administered prior to implantation of MC-38-CEA cells followed by administration of anti-PD-1 antibody. CEA-specific T-cell responses were measured by flow cytometry and ELISPOT. Dynamic co-culture of splenocytes with tumor cells was conducted to analyze anti-tumor activities. Tumor infiltration by lymphocytes was measured by IHC. Tumor volume and overall survival were also recorded. Ad-CEA combined with anti-PD-1 antibody showed greater anti-tumor activity compared with either alone. The combination also increased T-cell infiltration but decreased Tregs. Combining Ad-CEA vaccination with anti-PD-1 antibody enhanced anti-tumor activity and immune responses.
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http://dx.doi.org/10.2217/imt-2019-0055DOI Listing
August 2019

Safety of Nivolumab plus Low-Dose Ipilimumab in Previously Treated Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer.

Oncologist 2019 11 30;24(11):1453-1461. Epub 2019 May 30.

Emory University Winship Cancer Institute, Atlanta, Georgia, USA.

Background: Early detection and management of treatment-related adverse events (TRAEs) in patients receiving immune checkpoint inhibitors may improve outcomes. In CheckMate 142, nivolumab (3 mg/kg) plus low-dose ipilimumab (1 mg/kg) provided durable clinical benefit (objective response rate [ORR] 55%, median duration of response not reached, 12-month overall survival [OS] rate 85%) and manageable safety for previously treated microsatellite instability-high and/or mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC). In-depth safety and additional efficacy outcomes from CheckMate 142 are presented.

Materials And Methods: Safety assessments included frequency of TRAEs, select TRAEs (sTRAEs), and immune-mediated adverse event incidences; time to onset (TTO); time to resolution (TTR); immune-modulating medication (IMM) use; dose delay; and sTRAE occurrence after resuming therapy. Efficacy assessments included ORR and survival analyses in patients with sTRAEs with or without concomitant IMM treatment and patients without sTRAEs.

Results: Among 119 patients, 25%, 23%, 19%, 5%, 5%, and 29% experienced an endocrine, gastrointestinal, hepatic, pulmonary, renal, or skin sTRAE, respectively; the majority (57%) were grade 1/2. sTRAEs occurred early (median TTO, 5.2-12.6 weeks). Nonendocrine sTRAEs resolved in most (>71%) patients (median TTR, 1.5-9.0 weeks). IMMs were used to manage sTRAEs in 22%-56% of patients (most resolved). Of patients with dose delay because of sTRAEs, 25 of 29 resumed treatment. Patients with or without sTRAEs had comparable ORR (57% vs. 52%) and 12-month OS rates (93% vs. 75%). Similar results were observed in patients with or without sTRAEs regardless of IMM use (ORR 52% vs. 57%; OS rates 87% vs. 82%).

Conclusion: The benefit-risk profile of nivolumab plus low-dose ipilimumab provides a promising treatment option for patients with previously treated MSI-H/dMMR mCRC.

Implications For Practice: Nivolumab (NIVO) plus low-dose (1 mg/kg) ipilimumab (IPI) received U.S. Food and Drug Administration approval for patients with microsatellite instability-high and/or mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) that progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan based on results from CheckMate 142. In this safety analysis, the majority of select treatment-related adverse events (sTRAEs) occurred early, were managed using evidence-based treatment algorithms, and resolved. Efficacy outcomes were comparable between patients with or without sTRAEs regardless of the use of concomitant immune-modulating medications. The benefit-risk profile of NIVO + low-dose IPI provides a promising treatment option for MSI-H/dMMR mCRC.
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http://dx.doi.org/10.1634/theoncologist.2019-0129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853093PMC
November 2019

Results from a Phase IIb, Randomized, Multicenter Study of GVAX Pancreas and CRS-207 Compared with Chemotherapy in Adults with Previously Treated Metastatic Pancreatic Adenocarcinoma (ECLIPSE Study).

Clin Cancer Res 2019 Sep 24;25(18):5493-5502. Epub 2019 May 24.

The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland.

Purpose: Limited options exist for patients with advanced pancreatic cancer progressing after 1 or more lines of therapy. A phase II study in patients with previously treated metastatic pancreatic cancer showed that combining GVAX pancreas (granulocyte-macrophage colony-stimulating factor-secreting allogeneic pancreatic tumor cells) with cyclophosphamide (Cy) and CRS-207 (live, attenuated expressing mesothelin) resulted in median overall survival (OS) of 6.1 months, which compares favorably with historical OS achieved with chemotherapy. In the current study, we compared Cy/GVAX + CRS-207, CRS-207 alone, and standard chemotherapy in a three-arm, randomized, controlled phase IIb trial.

Patients And Methods: Patients with previously treated metastatic pancreatic adenocarcinoma were randomized 1:1:1 to receive Cy/GVAX + CRS-207 (arm A), CRS-207 (arm B), or physician's choice of single-agent chemotherapy (arm C). The primary cohort included patients who had failed ≥2 prior lines of therapy, including gemcitabine. The primary objective compared OS between arms A and C in the primary cohort. The second-line cohort included patients who had received 1 prior line of therapy. Additional objectives included OS between all treatment arms, safety, and tumor responses.

Results: The study did not meet its primary efficacy endpoint. At the final study analysis, median OS [95% confidence interval (CI)] in the primary cohort ( = 213) was 3.7 (2.9-5.3), 5.4 (4.2-6.4), and 4.6 (4.2-5.7) months in arms A, B, and C, respectively, showing no significant difference between arm A and arm C [ = not significant (NS), HR = 1.17; 95% CI, 0.84-1.64]. The most frequently reported adverse events in all treatment groups were chills, pyrexia, fatigue, and nausea. No treatment-related deaths occurred.

Conclusions: The combination of Cy/GVAX + CRS-207 did not improve survival over chemotherapy. (ClinicalTrials.gov ID: NCT02004262).
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http://dx.doi.org/10.1158/1078-0432.CCR-18-2992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7376746PMC
September 2019

Functional CD3CD8PD1 T Cell Accumulation and PD-L1 Expression Increases During Tumor Invasion in DCIS of the Breast.

Clin Breast Cancer 2019 10 16;19(5):e617-e623. Epub 2019 Apr 16.

Department of Surgery, Duke University Medical Center, Durham, NC. Electronic address:

Background: The changes in T cell subsets and programmed death ligand 1 (PD-L1) expression during the transition from ductal carcinoma in situ (DCIS) to early invasive breast cancer had not been well studied.

Patients And Methods: A total of 85 DCIS patients were classified into 49 DCIS (clinical stage: Tis, noninvasive) and 36 with a minimally infiltrating lesion (MIL; < 5 mm; clinical stage: T1a). We explored the quantitative alterations of T-cell markers and PD-L1 in these groups using the Opal multi-immunohistochemistry technique.

Results: We observed increased infiltration of CD3-positive (CD3)CD8 programmed death 1 (PD1)-negative T cells and higher PD-L1 expression in DCIS with MIL. Elevated PD1 expression correlated with PD-L1 expression in MIL and DCIS.

Conclusion: We conclude that during the transition from DCIS to an invasive lesion, the host cytolytic T cells begin interacting with the tumor and destroy the tumor tissue, leading to an adaptive upregulation of PD-L1 and tumor protection against immune destruction.
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http://dx.doi.org/10.1016/j.clbc.2019.04.001DOI Listing
October 2019

Nivolumab Alone and With Ipilimumab in Previously Treated Metastatic Urothelial Carcinoma: CheckMate 032 Nivolumab 1 mg/kg Plus Ipilimumab 3 mg/kg Expansion Cohort Results.

J Clin Oncol 2019 07 17;37(19):1608-1616. Epub 2019 May 17.

14 Memorial Sloan Kettering Cancer Center, New York, NY.

Purpose: CheckMate 032 is an open-label, multicohort study that includes patients with unresectable locally advanced or metastatic urothelial carcinoma (mUC) treated with nivolumab 3 mg/kg monotherapy every 2 weeks (NIVO3), nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks (NIVO3+IPI1), or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks (NIVO1+IPI3). We report on the expanded NIVO1+IPI3 cohort and extended follow-up for the NIVO3 and NIVO3+IPI1 cohorts.

Methods: Patients with platinum-pretreated mUC were enrolled in this phase I/II multicenter study to receive NIVO3, NIVO3+IPI1, or NIVO1+IPI3 until disease progression or unacceptable toxicity. Primary end point was investigator-assessed objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, including duration of response.

Results: Seventy-eight patients were treated with NIVO3 (minimum follow-up, 37.7 months), 104 with NIVO3+IPI1 (minimum follow-up, 38.8 months), and 92 with NIVO1+IPI3 (minimum follow-up, 7.9 months). Objective response rate was 25.6%, 26.9%, and 38.0% in the NIVO3, NIVO3+IPI1, and NIVO1+IPI3 arms, respectively. Median duration of response was more than 22 months in all arms. Grade 3 or 4 treatment-related adverse events occurred in 21 (26.9%), 32 (30.8%), and 36 (39.1%) patients treated with NIVO3, NIVO3+IPI1, and NIVO1+IPI3, respectively. Grade 5 treatment-related pneumonitis occurred in one patient each in the NIVO3 and NIVO3+IPI1 arms.

Conclusion: With longer follow-up, NIVO3 demonstrated sustained antitumor activity alone and in combination with ipilimumab. NIVO1+IPI3 provided the greatest antitumor activity of all regimens, with a manageable safety profile. This result not only supports additional study of NIVO1+IPI3 in mUC, but demonstrates the potential benefit of immunotherapy combinations in this disease.
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http://dx.doi.org/10.1200/JCO.19.00538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879315PMC
July 2019

Prospective randomized comparative study on rivaroxaban and LMWH for prophylaxis of post-apheresis thrombosis in adoptive T cell immunotherapy cancer patients.

J Thromb Thrombolysis 2019 May;47(4):505-511

Department of Surgery, Duke University Medical Center, 203 Research Drive, Suite 433, Box 2606, Durham, NC, 27710, USA.

Autologous adoptive T cell immunotherapy has been recognized as an effective treatment for cancer patients. The initial qualified lymphocytes is the core element determining the immunotherapeutic outcomes clinically. Cell separator based apheresis procedure is an optimal procedure to collect adequate mono-nucleated lymphocytes to generate efficient ex vivo T cell expansions; however, potential catheter-associated femoral vein thrombosis at post-apheresis might rise an additional deteriorated morbidity for cancer patients. The emerging prophylactic medications are required at such circumstances. Therefore this study was designed to compare the prophylactic effects of rivaroxaban versus low molecular weight heparin (LMWH) in patients who had exposed during the femoral vein catheterization for apheresis. 74 Patients were randomized 1:1:1 into three groups: subcutaneous injection of LMWH, Fraxiparine (n = 23) (0.4 ml, 3800 IU/day) for 2 days, oral rivaroxaban 10 mg/d (n = 26), and oral rivaroxaban 20 mg/d (n = 25) for consecutive 2 days. The primary endpoint was to compare the venous thromboembolism (VTE) occurrence cases in one month post catheterization. There were 4 cases confirmed VTE occurrence in LMWH group with contrast to 1 case in rivaroxaban 10 mg administration group. None was seen in rivaroxaban 20 mg group (P = 0.02 as the comparison with LMWH). Meantime there was no bleeding events occurrence afterwards. Oral rivaroxaban 20 mg/day was recommendable to be considered which superior to LMWH. Although these limited data and patient volume reached the statistical difference which was able to provide the evidence proofed to compare the potency of those two anticoagulants, it could be regarded as the preliminary data provide the clinical results for cancer patients who were placed in the condition of apheresis and subsequently undergone adoptive T cell immunotherapy.Trial registration ClinicalTrials.gov identifier, NCT03282643. Registered 16 February 2016, http://www.ClinicalTrials.gov/ NCT03282643.
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http://dx.doi.org/10.1007/s11239-019-01844-7DOI Listing
May 2019

A Phase I-II Study Using Rexin-G Tumor-Targeted Retrovector Encoding a Dominant-Negative Cyclin G1 Inhibitor for Advanced Pancreatic Cancer.

Mol Ther Oncolytics 2019 Mar 14;12:56-67. Epub 2018 Dec 14.

Cancer Center of Southern California, Santa Monica, CA, USA.

Rexin-G is a replication-incompetent retroviral vector displaying a cryptic -binding peptide for targeting abnormal Signature () proteins in tumors and encoding a dominant-negative human cyclin G1 construct. Herein we report on the safety and antitumor activity of escalating doses of Rexin-G in gemcitabine-refractory pancreatic adenocarcinoma, with one 10-year survivor. For the safety analysis (n = 20), treatment-related grade 1 adverse events included fatigue (n = 6), chills (n = 2), and headache (n = 1), with no organ damage and no DLT. No patient tested positive for vector-neutralizing antibodies, antibodies to gp70, replication-competent retrovirus (RCR), or vector integration into genomic DNA of peripheral blood lymphocytes (PBLs). For the efficacy analysis (n = 15), one patient achieved a complete response (CR), two patients had a partial response (PR), and 12 had stable disease (SD). Median progression-free survival (PFS) was 2.7, 4.0, and 5.6 months at doses 0-I, II, and III, respectively. Median overall survival (OS) and 1-year OS rate at dose 0-I were 4.3 months and 0%, and at dose II-III they were 9.2 months and 33.3%. To date, one patient is still alive with no evidence of cancer 10 years after the start of Rexin-G treatment. Taken together, these data suggest that Rexin-G, the first targeted gene delivery system, is uniquely safe and exhibits significant antitumor activity, for which the FDA granted fast-track designation.
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http://dx.doi.org/10.1016/j.omto.2018.12.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6348982PMC
March 2019