Checkpoint Inhibitor Therapy In Patients Research Articles

Peripheral PD1-positive CD4 T-Lymphocyte Count Can Predict Progression-free Survival in Patients With Non-small Cell Lung Cancer Receiving Immune Checkpoint Inhibitor.

Little information is available about the association between peripheral T-lymphocyte expression of programmed cell death protein 1 (PD1) and the efficacy of immune checkpoint inhibitor therapy in patients with non-small cell lung cancer (NSCLC). We analyzed the PD1 and cytotoxic T-lymphocyte associated protein 4 (CTLA4) expression in peripheral blood T-lymphocytes of patients with NSCLC receiving immune checkpoint inhibitor therapy. Patients with NSCLC who were scheduled to receive treatment with immune checkpoint inhibitors were prospectively enrolled in this study between November 2017 and November 2018. Peripheral blood samples were obtained within 1 week before or after the initiation of treatment with an immune checkpoint inhibitor. Flow cytometry was conducted in 19 patients. Patients were treated with nivolumab, pembrolizumab, or atezolizumab. The group with a high percentage of PD1+CD4+ T-lymphocytes relative to the total CD4+ T-lymphocyte count had a longer progression-free survival [median=6.0 (95% confidence intervaI=0.5-not estimated) months] than the group with a low percentage of PD1+CD4+ T-lymphocytes [median=1.1 (95% confidence intervaI=0.4-5.0) months; p=0.034, log-rank test]. However, no significant associations were detected with the percentages of CTLA4+CD4+, PD1+CD8+ or CTLA4+CD8+ T-lymphocytes in the peripheral blood. A high percentage of peripheral CD4+PD1+ T-lymphocytes was associated with a longer progression-free survival in patients receiving treatment with an immune checkpoint inhibitor. The systemic immune system may have an influence on the efficacy of immune checkpoint inhibitor therapy in patients with NSCLC.

Paraneoplastic and Therapy-Related Immune Complications in Thymic Malignancies.

The thymus is a key organ involved in establishing central immune tolerance. Thymic epithelial tumors (TETs) include thymomas and thymic carcinomas. Thymomas, which are histologically distinct from thymic carcinomas, lead to dysregulated thymopoiesis via decreased thymic epithelial expression of AIRE and MHC Class II, as well as via alterations in thymic architecture, thereby resulting in autoimmune complications that manifest as paraneoplastic disorders (PNDs). Although progress has been made in elucidating the mechanisms underlying thymoma-associated PNDs, there remains a great need to further define the underlying mechanisms and to identify additional immune biomarkers, such as novel antibodies (in "seronegative" cases) to facilitate diagnosis and monitoring of patients. In addition, a better understanding of the pathogenesis of PNDs could lead to improved treatment strategies for both thymomas and their immune complications. In advanced, refractory cases of TETs (both thymoma and thymic carcinoma), additional therapeutic approaches are needed. Immune checkpoint inhibitors have revolutionized the treatment of several malignancies and hold promise in the treatment of TETs; however, the risks for immune-related adverse events (especially for inducing PNDs as well as in the setting of pre-existing PNDs) underscore the need to optimize patient selection and improve clinical management before there can be widespread acceptance of checkpoint inhibitor therapy in patients with TETs.

Monitoring Efficacy of Checkpoint Inhibitor Therapy in Patients with Non-Small-Cell Lung Cancer

Aim: Radiological criteria alone do not reflect the entire population benefitting from checkpoint inhibitor therapy (CIT). This study aimed to detect patterns to assess CIT efficacy in non-small-cell lung cancer (NSCLC) patients. Materials & methods: We evaluated clinical, radiological and laboratory parameters in a retrospective cohort of NSCLC patients treated with nivolumab. Results:A total of51 patients were included in the analysis. Most single parameters failed to reflect treatment benefit. Three laboratory parameters (lactate dehydrogenase, C-reactive protein and the neutrophil/lymphocyte ratio) combined in a weighted score could predict benefit with a sensitivity of 92.3% and a hazard ratio of 0.31 (95% CI: 0.16-0.59) in an early phase of therapy. Sorting patients by score showed a 1-year survival of 36% in those predicted as not benefitting versus 68% in those predicted to benefit. Conclusion: A weighted score integrating common serum markers could help detect patients benefitting from checkpoint inhibitors during ongoing CIT.

Complete response to ipilimumab and nivolumab therapy in a patient with extensive extrapulmonary high-grade small cell carcinoma of the pancreas and HIV infection

BackgroundImmune checkpoint inhibitors (CPIs) have shown promising results in many solid tumors. There are limited data on the safety and efficacy of these drugs in HIV infected patients as they have traditionally been excluded from CPIs clinical trials.Case presentationWe present a case of an HIV-positive patient with extensive extrapulmonary high-grade small cell carcinoma who was treated with dual CPIs (nivolumab and ipilimumab) with a complete response to therapy and with a manageable safety profile. We performed a comprehensive literature review identifying 62 total HIV positive cases treated with CPIs showing this to be a potentially safe option in HIV-positive patients.ConclusionHIV infection is not an absolute contraindication to CPI therapy. Our case and others provide justification for ongoing trials of CPI therapy in patients with HIV infection, a group that has traditionally been excluded from clinical trials.

Immunotherapy in metastatic melanoma: When is it safe to stop?

e21518Background: Optimal duration of immune checkpoint inhibitor therapy in patients with Metastatic Melanoma remains undefined. Current practice mirrors the approach taken in clinical trials reco...

The outcome of checkpoint inhibitor therapy in patients with cancer and solid organ transplant: A systematic review of the literature.

41 Background: Solid organ transplant recipients have been excluded from Checkpoint inhibitors (CPI) clinical trials because of the concern of allo-immunity and possible organ rejection. Methods: We searched 5 databases through September 2017. Studies describing the use of CPI to treat cancer in solid organ transplant Patients (pts), and provided detailed description of each case were included. Results: Sixteen publications met inclusion criteria, reporting on 19 cases. Median age of pts was 59 (14-77) yrs and 74% were male. Cancer types included melanoma (n=11), cutaneous squamous cell carcinoma (ca) (n=3), non-small cell lung ca and hepatocellular ca (n=2 each), and duodenal ca (n=1). Median time to start CPI after organ transplant was 11 (1-25) yrs. Nivolumab (nivo) was used in 53%, ipilimumab (ipi) in 26%, and pembrolizumab (pem) in 21%. Most pts were maintained on low dose prednisone (≤ 10 mg), mTOR inhibitors, and other immunosuppressives prior to initiating CPI. Graft rejection occurred in 10 of 19 pts (7/12 kidney, 2/5 liver, and 1/2 heart transplants), 90% after receiving anti PD-1, and CPI was discontinued. Median time to rejection was 21 (5-60) days, and obtained biopsies were suggestive of a T-cell mediated rejection process. Only a cardiac transplant recipient with a bioposy proven cellular rejection after nivo, had improved ejection fraction after pulse steroids. Aside from rejection no other immune related adverse events (irAEs) reported. Nivo re-challenge was recommended for a kidney recipient 12 weeks after the rejection process, and the pt had partial tumor response but remained on hemodialysis. Of the 9 pts who had no rejection, 4 had irAEs (hepatitis, colitis, pneumonitis, and dermatitis), including 3 who required high-dose steroids with subsequent improvement, and the remaining 5 pts did not experience any irAEs. Clinical benefit rate was 57% of all pts. Two pts with liver transplants died within 1 month of nivo treatment secondary to acute liver rejection, and 2 others died because of progressive cancer. Conclusions: CPI seem to be associated with high rate of rejection. Multi-institutional collaborative studies are warranted to enhance our understanding of the pathogenesis and plan optiomal therapy that maintain graft tolerance without dampening antitumor clinical benefits.

Endocrine adverse effects after immune checkpoint inhibitor therapy in patients with metastatic melanoma: Experience from a single tertiary level centre

Endocrine adverse effects after immune checkpoint inhibitor therapy in patients with metastatic melanoma: Experience from a single tertiary level centre

Salvage combination ipilimumab and nivolumab after failure of prior checkpoint inhibitor therapy in patients with advanced melanoma.

e21009 Background: The combination of Ipilimumab and Nivolumab is standard initial therapy in patients with advanced melanoma based on trials involving treatment-naïve patients. The benefit in those previously managed with checkpoint monotherapy is not well defined. Methods: We identified metastatic melanoma patients from our Immunotherapy database managed with combination Ipilimumab/Nivolumab after progression on prior checkpoint monotherapy. Baseline clinical factors, treatment history, combination therapy outcome by RECIST v1.1 and toxicity data were collected. Descriptive statistics were used to summarize the data. Given the small sample size and limited numbers of deaths, it is too early to look for preliminary associations between outcomes and clinicopathologic factors. Results: We identified 19 patients treated with combination Ipilimumab/Nivolumab after progression on prior checkpoint monotherapy. The cohort included 15 men and 4 women with an average age of 63 years. Thirteen patients had M1c disease, and 7 had a BRAF mutation. Patients had received up to four lines of prior immunotherapy including 9 treated with both prior anti-PD1 and anti-CTLA4 monotherapy. Seven patients completed all four doses of combination therapy with 6 proceeding onto maintenance nivolumab. Eight patients stopped treatment due to toxicity and 4 due to progressive disease. Thirteen patients had clinically significant toxicity, with rash, colitis, hepatitis, and hypophysitis reported most frequently. There were no treatment-related deaths. Overall, 2/19 patients (10.5%, 95% CI [1.3% to 33.1%]) had an objective response (CR+PR) and 9/19 patients (47.4%, 95% CI [24.5% to 71.1%]) had disease control (CR+PR+SD). Four of the patients had stable disease for over 6 months. Six of the 19 patients went on to receive subsequent treatment. Median follow-up for patients still alive was 7 months (range 1 to 20 months) and median survival was not reached. Six-month survival was 68.5% (95% CI [39.3% to 85.8%]) Conclusions: The combination of Ipilimumab and Nivolumab can result in melanoma control in patients with progression on prior checkpoint monotherapy with an expected toxicity profile.

Neoadjuvant and adjuvant vaccine therapy with or without PD1 checkpoint inhibitor therapy in patients with resectable pancreatic cancer: a trial in progress

Objective: Our group has developed an irradiated GM-CSF secreting allogenic pancreatic adenocarcinoma (PDA) vaccine (GVAX). Multiple trials have shown GVAX to be safe with a survival benefit associated with enhancement of intratumoral antigen specific T-cells. The PDA microenvironment inhibits the most effective immune response. Our preclinical model suggests GVAX primes the PDA microenvironment for PD-1 checkpoint inhibitor therapy (nviolumab), and in combination vaccine-induced anti-tumor T-cell responses may be enhanced. Methods: 50 patients with resectable PDA will be enrolled and randomized to receive neoadjuvant treatment with GVAX plus cyclophosphamide (Cy/GVAX) or Cy/GVAX combined with nivolumab. All subjects will receive 5 additional adjuvant immunotherapy treatments. A core-needle biopsy obtained prior to first treatment, along with the surgical specimen will be used for evaluation of IL17A expression in vaccine-induced lymphoid aggregates. Safety, disease free survival (DFS) and overall survival (OS) will be assessed. PD1 pathways and vaccine-induced immune regulatory signatures in the microenvironment will be evaluated through immunohistochemistry and mRNA sequencing. Results: Accrual has initiated and enrolled 6 subjects. All 6 have received neoadjuvant immunotherapy and undergone pancreatectomy, with 5 receiving the second adjuvant immunotherapy treatments. Tumor infiltrating immune cells have been collected with initiation of preliminary staining of CD3, CD4, CD8, CD65 and FOXP3. Conclusion: We will continue patient enrollment and analysis of immune parameters. Surgical outcomes, DFS and OS will be assessed as the study matures. Altering the immune environment with combination immunotherapy is a novel approach for the treatment of patients with PDA and other non-immunogenic cancers.

OA18.03 Safety and Clinical Activity of Avelumab (MSB0010718C; Anti-PD-L1) in Patients with Advanced Thymic Epithelial Tumors (TETs)

Avelumab (MSB0010718C) is a fully human, IgG1 anti-PD-L1 antibody under clinical development. We report safety and clinical activity in patients with relapsed TETs enrolled in a phase I trial (NCT01772004). Patients previously treated with one or more standard therapies, no prior immune checkpoint inhibitors, and with no history of autoimmune disease were eligible. Treatment consisted of avelumab at doses of 10-20 mg/kg iv q2 weeks until disease progression or toxicity. Responses were assessed q6 weeks by RECIST 1.1. Correlative studies included evaluation of tumor cell PD-L1 expression and peripheral blood immune subset analysis. 7 patients with thymoma and 1 with thymic carcinoma (TC) were treated with avelumab; 3 patients with thymoma (2 B3, 1 B2/B3) received avelumab 20 mg/kg; 4 patients with thymoma (1 B1, 3 B2) and 1 TC received 10 mg/kg. Two (29%) patients with thymoma had a confirmed partial response (PR;1 at 20 mg/kg, and 1 at 10 mg/kg), 2 (29%) had unconfirmed PRs, 2 (29%) stable disease (SD) and 1 (14%) progressive disease; the TC patient had SD. Most adverse events (AEs) were mild (grade 1 or 2). Grade 3 and 4 AEs were observed in 3 (38%) patients each, and included potential immune-related AEs (irAEs) in 5 cases. irAEs resolved completely with oral steroids in 3 patients, and incompletely in 1 patient. One patient required cyclosporine A for treatment of irAEs. All 4 responders experienced irAEs (myositis in 3 patients, all after 1 dose of avelumab, and enteritis in 1 patient). Pre- and post-treatment tumor biopsies were available for analysis of PD-L1 expression and intratumoral immune infiltrates from three patients treated at 20 mg/kg. In one case the post-treatment biopsy showed necrotic tissue with no viable tumor. In the other two cases diffuse, membranous PD-L1 staining of epithelial cells was seen in both pre- and post-treatment biopsies. The immune infiltrate consisted of immature T cells in pre-treatment tumor samples in both cases. The post-treatment biopsy showed continued presence of immature T cells in one case and a mature CD8+ T cell phenotype in the other case. Decreased CTLA4+ regulatory T cells and decreased ratio of granulocytic vs. monocytic myeloid-derived suppressor cells was seen post-treatment at the 20mg/kg dose. Avelumab is active in patients with recurrent thymoma. Strategies need to be developed to reduce the risk of development of irAEs in response to immune checkpoint inhibitor therapy in patients with thymoma.

P2.06-014 Phase 2 Study of Glesatinib or Sitravatinib with Nivolumab in Non-Small Cell Lung Cancer (NSCLC) after Checkpoint Inhibitor Therapy: Topic: Phase II + NK

Combination therapy with agents that target the molecular and cellular mechanisms of resistance to checkpoint inhibitor therapy (CIT) is a rational approach to restoring or improving the efficacy of CIT in patients with immunotherapy resistant NSCLC. Glesatinib, a tyrosine kinase inhibitor (TKI), which targets Axl, MER and MET RTKs expressed on macrophages and antigen-presenting-cells within the tumor microenvironment (TME), may reverse the immunosuppressive TME and enhance anti-tumor T and NK cell responses by enhancing antigen presentation and T cell effector function. Sitravatinib, also a TKI, which targets VEGFR2 and KIT as well as Axl, MER and MET, may further enhance anti-tumor activity by VEGFR2 and KIT inhibition mediated reduction of regulatory T cells and myeloid-derived suppressor cells (MDSCs). Given these pleiotropic immune activating effects, the combination of glesatinib or sitravatinib with nivolumab is a rational approach to restoring or enhancing the clinical activity of CIT in patients with immunotherapy resistant NSCLC. This open-label Phase 2 study evaluates the tolerability and clinical activity of the investigational agents, glesatinib or sitravatinib in combination with nivolumab in separate cohorts of patients with non-squamous NSCLC who have experienced progression of disease on or after treatment with CIT. The study begins with a limited dose escalation evaluation of each investigational agent in combination with nivolumab to determine the dose levels to be used in Phase 2. The primary objective is to assess the clinical activity of the combination regimens using the Objective Response Rate (ORR) by RECIST 1.1. Other objectives include safety, tolerability, pharmacokinetics and changes in circulating and tumor cell PD-L1, circulating and tumor infiltrating immune cell populations, cytokines and gene expression signatures. Enrollment into each Phase 2 treatment arm is stratified by prior outcome of CIT (e.g., clinical benefit versus progression of disease in ≤12 weeks). The investigational agents are administered orally in continuous regimens; nivolumab is administered intravenously, 3 mg/kg every 2 weeks. The sample sizes for the treatment arms are based on two-stage Simon Optimal Designs. Status: The US IND opened in June 2016. Section not applicable. Section not applicable.

A case of meningomyelocele in a kindred with multiple cases of spondylolisthesis and spina bifida occulta.

<h3>Background</h3> The use of immune checkpoint inhibitors (ICI) has increased significantly in the past five years, along with the number of available drugs and regimens. ICIs have dramatically increased survival in cancer patients, however, there has been data to show that they have reduced efficacy in the presence of antibiotics.¹ Antibiotic use prior and during ICI therapy was associated with worsening clinical outcomes in patients with renal cell carcinoma,² melanoma,³ and non-small-cell-lung-cancer.⁴ Specifically, exposure within 60 days of initiation of ICIs in NSCLC seemed most detrimental, however, some studies have suggested that antibiotics disrupt intestinal microflora for up to six months.^{5 6} Therefore, we hypothesized that the duration of the antibiotic effect on ICI efficacy may be present for a longer duration. <h3>Methods</h3> The electronic medical record was queried at the University of Cincinnati Medical Center for the administration of ICIs and antibiotics. Data was collected on the use, type, and duration of antibiotics before ICI use after administration with relevant demographic and clinicopathologic variables including treatment type, cancer type, staging information, and clinical course including subsequent antibiotic use. Univariant (Fischer’s Exact) and multivariant analysis (multiple logistic regression) were conducted and survival analysis was determined according to log-rank testing. <h3>Results</h3> 217 patients were examined. The median age was 64 (range 22-93), 38% were female, 73% had ECOG 0-1, and 77% were white. Cancer types included melanoma 24%, non-small cell lung cancer (NSCLC) 34%, small cell lung cancer 2%, renal cancer 11%, urothelial cancer 10%, head and neck cancers 11%, and 16% other primaries. 20% remained on ICI at the time of data entry. The most common ICIs were pembrolizumab, nivolumab, followed by ipilimumab-nivolumab, ipilimumab, and durvalumab. 81 patients of 218 received antibiotics within 6 months of receiving checkpoint inhibitors. Of antibiotics administered, the most common classes were cephalosporins (86%), fluoroquinolones (28%), and glycopeptides (23%) with substantial overlap. Overall survival and progression-free survival was improved for those who did not receive antibiotics prior to ICI therapy (median OS 6.5 vs. 2.3 years, HR 0.36, p&lt;0.0001; median PFS 1.1 vs 0.5 years, HR 0.6, p=0.0027) (figure 1 and 2 respectively). Linear regression showed no significant association between antibiotic use prior to ICI use and age, sex, race, ICI type, or ECOG status. <h3>Conclusions</h3> This data adds to the growing body of knowledge that the use of antibiotics prior to ICI treatment leads to inferior overall and progression-free survival. <h3>Acknowledgements</h3> We would like to thank the Roman Jandarov, UC Cancer Center, the University of Cincinnati Division of Hematology and Oncology, Department of Internal Medicine of the University of Cincinnati, and the University of Cincinnati Medical Center for their continued support. <h3>Ethics Approval</h3> IRB 2019-0610 <h3>References</h3> Pinato DJ, Gramenitskaya D, Altmann DM, Boyton RJ, Mullish BH, Marchesi JR, et al. Antibiotic therapy and outcome from immune-checkpoint inhibitors. <i>J Immunother Cancer</i> 2019;<b>7</b>:287. Ueda K, Yonekura S, Ogasawara N, Matsunaga Y, Hoshino R, Kurose H, et al. The impact of antibiotics on prognosis of metastatic renal cell carcinoma in japanese patients treated with immune checkpoint inhibitors. <i>Anticancer Res</i> 2019;<b>39</b>:6265–71. Elkrief A, El Raichani L, Richard C, Messaoudene M, Belkaid W, Malo J, et al. Antibiotics are associated with decreased progression-free survival of advanced melanoma patients treated with immune checkpoint inhibitors. <i>Oncoimmunology</i> 2019;8:e1568812. Ruiz-Patiño A, Barrón F, Cardona AF, Corrales L, Mas L, Martín C, et al. Antibiotics impair immune checkpoint inhibitor effectiveness in Hispanic patients with non-small cell lung cancer (AB-CLICaP). <i>Thorac Cancer</i> 2020;(9):2552-2560. Pinato DJ, Howlett S, Ottaviani D, Urus H, Patel A, Mineo T, et al. Association of prior antibiotic treatment with survival and response to immune checkpoint inhibitor therapy in patients with cancer. <i>JAMA Oncol</i> 2019;5(12):1774-1778. Panda S, Khader IE, Casellas F, Vivancos JL, Cors MG, Santiago A, et al. Short-term effect of antibiotics on human gut microbiota. <i>PLoS ONE</i> 2014;9.