scholarly journals 6 Immune correlates of clinical benefit in patients with HPV-associated malignancies treated with bintrafusp alfa

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A6-A6
Author(s):  
Yo-Ting Tsai ◽  
Renee Donahue ◽  
Nicole Toney ◽  
Julius Strauss ◽  
James Gulley ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Clinical Benefit ◽  
Predictive Biomarkers ◽  
Cooperative Research ◽  
Open Label ◽  
Hpv 16 ◽  
Link Type ◽  
Immune Correlates

BackgroundThe safety and efficacy of bintrafusp alfa, a first-in-class bifunctional fusion protein targeting TGFβ and PD-L1 pathways, have been demonstrated in patients with HPV-related cancers in an open-label, multicenter phase 1 trial (NCT02517398), and an open-label, single-center phase 2 trial (NCT03427411). The current study aimed to identify immune related biomarkers prior to and following 1 cycle of bintrafusp alfa that associate with clinical benefit.MethodsImmune parameters were compared in patients (n=65) deriving clinical benefit from bintrafusp alfa (defined as BOR of stable disease (SD) or better, which included SD, mixed, partial, and complete responses) versus patients with a BOR of progressive disease (PD). Peripheral blood was obtained from patients before and after 1 cycle of therapy, and evaluated for complete blood counts, plasma cytokines/soluble factors, 158 immune subsets, and T cells specific for HPV-16 E6 and E7.ResultsPrior to therapy, patients who developed a BOR of SD or better had lower counts of neutrophils, monocytes, and platelets, lower levels of TGF-β1 and sCD73, and higher levels of sCD27:sCD40L than patients with a BOR of PD. Lower baseline frequencies of MDSCs, monocytes, naïve CD4+ and CD8+ T cells, and CD8+ T cells that express CD73, an immune checkpoint associated with adenosine metabolism, were detected in patients with a BOR of SD or better than those with PD. Following 1 cycle of treatment, lymphocyte counts were reduced, while neutrophil counts and the NLR were increased, in patients with PD compared to those with a BOR of SD or better. IL-8, a cytokine involved in tumor progression and associated with reduced clinical benefit to immune checkpoint inhibitors, was increased in patients with PD compared to those with a BOR of SD or better, while conventional dendritic cells and CD8+ T cells expressing the proliferative marker ki67 were increased in patients with a BOR of SD or better compared to those with PD. Greater increases in the frequency and magnitude of HPV-16 specific CD8+ T-cells were also detected in individuals with a BOR of SD or better compared to PD.ConclusionsImmune profiling identified specific measures prior to therapy, as well as changes induced early after therapy (preceding restaging), that may serve as predictive biomarkers to identify patients with HPV-related cancers most likely to benefit from bintrafusp alfa. These findings also provide the rationale to combine bintrafusp alfa with other therapies including HPV-targeted therapeutic vaccines and agents that block IL-8 signaling.AcknowledgementsThis research was supported by the Intramural Research Program of the Center for Cancer Research, NCI, National Institutes of Health, and through a Cooperative Research and Development Agreement with EMD Serono Research & Development Institute and GSK.Ethics ApprovalThe study protocol was approved by ethics committees at all participating institutions, and each patient provided written informed consent before study enrollment.

scholarly journals 540 Baseline mTOR transcriptional signatures in CD8 T cells are associated with immune-related adverse events but not anti-tumor responses in patients receiving immune checkpoint inhibitors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A570-A570
Author(s):  
Chen Zhao ◽  
Matthew Mule ◽  
Andrew Martins ◽  
Iago Pinal Fernandez ◽  
Renee Donahue ◽  
...  
Keyword(s):  
T Cells ◽  
Adverse Events ◽  
Tumor Immunity ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Effector Memory ◽  
Link Type ◽  
Anti Tumor Activity

BackgroundImmune checkpoint inhibitors (ICIs) have changed the cancer treatment landscape, but immune-related adverse events (irAEs) can affect a wide range of tissues in patients receiving ICIs. Severe irAEs can be life-threatening or fatal and prohibit patients from receiving further ICI treatment. While the clinical features of irAEs are well documented, the pathological mechanisms and predictive biomarkers are largely unknown. In addition, there is a critical need to preserve ICI-induced anti-tumor immunity while controlling for irAEs, which requires deciphering molecular and cellular signatures associated specifically with irAEs beyond those more generally linked to anti-tumor immunity.MethodsTo unbiasedly identify immune cells and states associated with irAEs, we applied CITE-seq to measure transcripts and surface proteins (83 protein markers) from PBMCs collected from patients with thymic epithelial tumors before and after treatment with an anti-PD-L1 antibody (avelumab, NCT01772004, NCT03076554).ResultsSamples from 9 patients were analyzed. No patient had a history of pre-existing paraneoplastic autoimmune disease. Anti-tumor activity was observed in all cases, and 5 patients had clinical and/or biochemical evidence of immune-related muscle inflammation (myositis with or without myocarditis). Multilevel models applied within highly resolved cell clusters revealed transcriptional states associated with ICI response and more uniquely with irAEs. A total of 190,000 cells were included in the analysis after quality control. Most notably, CD45RA+ effector memory CD8 T cells with an mTOR transcriptional signature were highly enriched at baseline and post treatment in patients with irAEs.ConclusionsOur findings suggest the potential therapeutic avenues by using mTOR inhibitors to dampen autoimmune responses while potentially sparing anti-tumor activity, to prevent treatment discontinuation and improve clinical outcomes for cancer patients treated with ICIs.AcknowledgementsThis research was supported in part by the Intramural Research Program of the NCI (the Center for Cancer Research), NIAID and NIAMS, and through a Cooperative Research and Development Agreement between the National Cancer Institute and EMD Serono.Trial RegistrationNCT01772004, NCT03076554Ethics ApprovalThis study is approved by NCI institutional review board.

807 A multicenter open-label phase I/lb study of SO-C101 as monotherapy and in combination with pembrolizumab in patients with selected advanced/metastatic solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A856-A856
Author(s):  
Aurelien Marabelle ◽  
Stephane Champiat ◽  
Elena Garralda ◽  
Alberto Hernando ◽  
Filip Janku ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Dose Escalation ◽  
Cell Activation ◽  
Cd8 T Cell ◽  
Open Label ◽  
Link Type ◽  
Anti Cancer

BackgroundIL-15 is a member of the common y-chain family of cytokines that shares functional activities with IL-2. SO-C101is a superagonist fusion protein of IL-15 and the IL-15 receptor α sushi+ domain. SO-C101 stimulates the proliferation and the cytotoxic activity of NK cells and memory CD8+ T cells.In pre-clinical studies SO-C101 promoted expansion and activation of human, murine and cynomolgus monkey NK and CD8+ T cells. NK and CD8+ T cell activation correlated with potent monotherapy anti-cancer activity of SO-C101 in metastatic and solid tumor models. The combination of an anti-PD-1 or of anti-cancer monoclonal antibodies with SO-C 101 augmented the anti-tumor responses in mouse models. First clinical study was initiated in June 2019 to investigate SO-C101 as monotherapy and in combination with pembrolizumab.MethodsThe phase 1/1 b study currently on-going is a multicenter, open-label, dose escalation study for patients with selected advanced/metastatic solid tumors. The study consists of 2 parts: Part A - dose escalation of SO-C101 as monotherapy; Part B - dose escalation of SO-C101 in combination with pembrolizumab. Study objectives are to define the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of SO-C101 in both parts.ResultsAs of September 22nd, 19 subjects were treated in part A in 6 escalating dose levels, and 3 subjects were treated in part B, at dose level 1.SO-C101 was well tolerated. No DLT was observed, the main AEs related to SO-C101 were injection site reactions, fever, chills, flu-like syndrome, all G1- G2, and transient lymphopenia in 5 subjects, Grade 2 to 4, all resolved within few days.Preliminary PK results showed the PK profile to be dose-proportional, with a Tmax of approx. 5 – 6 hours after administration and T½ approx. 4 hours.Preliminary PD analysis showed dose dependent NK and CD8+ T cell activation.A preliminary efficacy signal has been observed in a patient refractory to anti-PD1 therapy, who showed a RECIST PR with initial 20% shrinkage of target lesions at 6 weeks and 49% shrinkage at 12 weeks on CT-scans.ConclusionsTo date, SO-C101 has been well tolerated, with a manageable toxicity and encouraging signs of clinical activity. The study will proceed to reach a RP2D in both monotherapy and combination with Pembrolizumab. Expansion of the study in selected indications is warranted.Trial Registration https://clinicaltrials.gov/ct2/show/NCT04234113?term=sotio&draw=3&rank=12The study was approved to proceed by FDA – IND 140011 -and by the sites ECs.Ethics ApprovalThe NCT04234113 clinical trial was approved by each investigational site health agency and ethical committee.ConsentWritten informed consent of patients was obtained prior enrollment in the NCT04234113 clinical trial.

Characterization of potential predictive biomarkers of response to nivolumab in CheckMate 141 in patients with squamous cell carcinoma of the head and neck (SCCHN).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 6050-6050 ◽  
Author(s):  
Fernando Concha-Benavente ◽  
Maura L. Gillison ◽  
George R. Blumenschein ◽  
Kevin Harrington ◽  
Jérôme Fayette ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Predictive Biomarkers ◽  
Treg Cells ◽  
Peripheral Blood Lymphocytes ◽  
Effector T Cells ◽  
Open Label ◽  
Effector Cells ◽  
Open Label Phase ◽  
Checkpoint Receptors

6050 Background: Nivolumab, an anti-programmed death-1 (PD-1) monoclonal antibody, demonstrated longer median overall survival (7.5 vs 5.1 months) and improved response (13.3% vs 5.8%) versus investigator choice chemotherapy (ICC) in patients with recurrent SCCHN after platinum failure in CheckMate 141 (NCT02105636), a randomized, open-label Phase 3 trial. We screened peripheral blood lymphocytes (PBL) to identify biomarkers which may predict response to nivolumab. Methods: Paired baseline (day 1) and on treatment (day 43) PBL samples (n = 36; 24 nivolumab; 12 ICC) were analyzed using multicolor flow cytometry and a non-competing anti-PD-1 antibody. Results were correlated with clinical outcome: responders (complete/partial response) and non-responders (stable or progressive disease). Results: Levels of CD8+ T cells at baseline and on treatment were higher in nivolumab responders compared to non-responders (23% vs 13%; P< 0.05). Interestingly, PD-1+ CD8+ and PD-1+ CTLA-4+ CD8+ effector T cells (likely exhausted T cells) decreased about 2-fold following nivolumab in both responders and non-responders ( P< 0.05), whereas, the decrease in CTLA-4+ CD8+ effector T cells following nivolumab was significant in responders only (8% vs 5%; P< 0.05). Levels of PD-1+ TIM-3+ CD8+ effector cells decreased following nivolumab in non-responders only (11% vs 7%; P< 0.05), a similar non-significant reduction was observed in responders. Levels of PD-1+ Tregs were lower in responders than non-responders at baseline (19% vs 33%; P< 0.01), and following nivolumab (12% vs 20%; P< 0.001). As in T-effector cell populations, PD-1+ Tregs decreased about 1.6-fold after nivolumab in both responders and non-responders ( P< 0.01). Interestingly, baseline Ki67+ Treg levels were lower in non-responders (28% vs 17%; P< 0.05). Conclusions: Response to nivolumab may be associated with higher levels of CD8+ T cells and CTLA-4+ CD8+ effector T cells, and lower PD-1+ CD8+ effector T cells and PD-1+ Tregs at baseline. Targeting both PD-1 and CTLA-4 axes is warranted in SCCHN to overcome suppressive signals in CD8+ effector T cells and in Treg cells expressing both checkpoint receptors. Clinical trial information: NCT02105636.

Characterization of potential predictive biomarkers of response to nivolumab in CheckMate-141 in patients with squamous cell carcinoma of the head and neck (SCCHN).

2017 ◽  
Vol 35 (7_suppl) ◽  
pp. 5-5 ◽  
Author(s):  
Robert L. Ferris ◽  
Fernando Concha-Benavente ◽  
George R. Blumenschein ◽  
Kevin J. Harrington ◽  
Jerome Fayette ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Predictive Biomarkers ◽  
Treg Cells ◽  
Peripheral Blood Lymphocytes ◽  
Effector T Cells ◽  
Open Label ◽  
Effector Cells ◽  
Open Label Phase ◽  
Checkpoint Receptors

5 Background: Nivolumab, an anti-programmed death-1 (PD-1) monoclonal antibody, demonstrated longer median overall survival (7.5 vs. 5.1 months) and improved response (13.3% vs. 5.8%) versus investigator choice chemotherapy (ICC) in patients with recurrent SCCHN after platinum failure in CheckMate 141 (NCT02105636), a randomized, open-label Phase 3 trial. We screened peripheral blood lymphocytes (PBL) to identify biomarkers which may predict response to nivolumab. Methods: Paired baseline (day 1) and on treatment (day 43) PBL samples (n=36; 24 nivolumab; 12 ICC) were analyzed using multicolor flow cytometry and a non-competing anti-PD-1 antibody. Results were correlated with clinical outcome: responders (complete/partial response) and non-responders (stable or progressive disease). Results: Levels of CD8+ T cells at baseline and on treatment were higher in nivolumab responders compared to non-responders (23% vs. 13%; p<0.05). Interestingly, PD-1+ CD8+ and PD-1+ CTLA-4+ CD8+ effector T cells (likely exhausted T cells) decreased about 2-fold following nivolumab in both responders and non-responders (p<0.05), whereas, the decrease in CTLA-4+ CD8+ effector T cells following nivolumab was significant in responders only (8% vs. 5%; p<0.05). Levels of PD-1+ TIM-3+ CD8+ effector cells decreased following nivolumab in non-responders only (11% vs. 7%; p<0.05), a similar non-significant reduction was observed in responders. Levels of PD-1+Tregs were lower in responders than non-responders at baseline (19% vs. 33%; p<0.01), and following nivolumab (12% vs. 20%; p<0.001). As in T effector cell populations, PD-1+ Tregs decreased about 1.6-fold after nivolumab in both responders and non-responders (p<0.01). Interestingly, baseline Ki67+ Treg levels were lower in non-responders (28% vs. 17%; p<0.05). Conclusions: Response to nivolumab may be associated with higher levels of CD8+ T cells and CTLA-4+ CD8+ effector T cells, and lower PD-1+ CD8+ effector T cells and PD-1+ Tregs at baseline. Targeting both PD-1 and CTLA-4 axes is warranted in SCCHN to overcome suppressive signals in CD8+ effector T cells and in Treg cells expressing both checkpoint receptors. Clinical trial information: NCT02105636.

Effect of NKTR-214 on the number and activity of CD8+ tumor infiltrating lymphocytes in patients with advanced renal cell carcinoma.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 454-454 ◽  
Author(s):  
Michael E. Hurwitz ◽  
Adi Diab ◽  
Chantale Bernatchez ◽  
Cara L. Haymaker ◽  
Harriet M. Kluger ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Tumor Infiltrating Lymphocytes ◽  
Poor Response ◽  
Post Treatment ◽  
Open Label

454 Background: Patients with low baseline CD8+ T-cells within the tumor microenvironment (TILs) have a poor response to immune checkpoint inhibitors. Agents designed to specifically activate and expand CD8+ T cells may improve clinical outcomes in patients with low TILs. NKTR-214 is a CD-122-biased agonist designed to provide sustained signaling through the heterodimeric IL-2 receptor pathway (IL-2Rβɣ) and preferentially activate and expand NK and effector CD8+ T cells over CD4+ T regulatory cells. Methods: A dose escalation, open-label, trial was initiated to assess the safety of NKTR-214 and explore immune changes in the blood and tumor microenvironment in patients with advanced solid tumors. NKTR-214 was administered IV in an outpatient setting with initial dosing at 0.003 mg/kg. Pre and post treatment blood and tumor samples were analyzed for immune phenotyping, gene expression, T cell receptor diversity, and changes in the tumor microenvironment by immunohistochemistry. Results: Among 25 patients dosed, 15 had RCC ([email protected]/kg, [email protected]/kg, and [email protected]/kg). Treatment with NKTR-214 was well tolerated and the MTD was not reached. One patient experienced DLTs (Gr3 syncope and hypotension) at 0.012 mg/kg. There were no immune-related AEs. Of 12 patients evaluable for response, 75% had SD at their first on treatment scan. Of 5 patients, who were immune checkpoint naïve with ≥ 1 prior TKI treatments, 3 experienced tumor shrinkage, 1 with PR per RECIST 1.1 (unconfirmed). Interrogation of the tumor microenvironment revealed many significant immunological changes post treatment, including increase in total and proliferating NK, CD8+, and CD4+ T cells. There was good correlation between increase in activated CD4+ and CD8+ T cells in peripheral blood with an increase in T cell infiltrates within the tumor tissue. Conclusions: NKTR-214 increased immune infiltration in the tumor and anti-tumor activity in patients who previously progressed on TKIs, with a favorable safety profile. The ability to alter the immune environment and increase PD-1 expression on effectors T cells may improve the effectiveness of anti-PD-1 blockade. A trial combining NKTR-214 and nivolumab is enrolling. Clinical trial information: 02869295.

Immunological and clinical profiles of patients with advanced or metastatic melanoma receiving immune checkpoint inhibitors to investigate potential biomarkers for immune-related adverse events.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14037-e14037
Author(s):  
Stephanie A. Berg ◽  
Michael Wesolowski ◽  
Brianna Burke ◽  
Courtney Regan Wagner ◽  
Joseph I Clark ◽  
...  
Keyword(s):  
T Cells ◽  
Adverse Events ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Molecular Mechanisms ◽  
Checkpoint Inhibitors ◽  
Rank Correlation ◽  
Predictive Biomarkers ◽  
Biological Variables

e14037 Background: Immune-related adverse events (irAEs) related to immune checkpoint inhibitors (ICIs) may target any organ and originate from autoreactive T cells injuring host tissues. There is a need to develop prognostic and predictive biomarkers to distinguish patients (pts) who will benefit from ICIs avoiding irAEs during treatment. We propose that irAEs are the result of many biological variables. We hypothesize that within each pts complex immunological profile, there may be patterns and associations which exist that represent a state of inflammation that is present prior to ICI therapy and hypothesize this could predict irAEs development. Methods: We created individual immunological profiles of 11 pts diagnosed with MM prior to receiving ICIs. Assays included: PBMC composition, circulating chemokines/cytokines, and IκB degradation status. CD4 and CD8 T cells were studied for their phenotype, activation status, proliferative capacity and cytolytic granules. Clinical data was collected on a larger MM pt cohort (n = 41) and descriptive statistics were utilized to characterize reported irAEs . Results: 110 input markers were utilized for immune signature analysis. 6 of the 11 pts reported grade 2+ irAEs after ICI therapy. The pro-inflammatory CCL13, CCL1, FLT-3, IL12p40, TRAIL, and granzyme b expressing CD4 T cells at steady state and after CD3 activation were significantly higher in pts with irAEs. Known inflammatory suspects (i.e., IL-2, IL-15, TNF-a or % CD8 T cells) were not associated with irAE development . A rank correlation test showed significant associations between the levels of these factors. irAEs were reported in 41% (n = 17) for our larger cohort, most frequently skin rash (7%), colitis (7%), hepatitis (7%) and thyroid dysfunction (4%). Conclusions: The immune signatures of pts with irAEs are highly heterogeneous and possess distinctive immunological patterns. Our results introduce possible molecular mechanisms that may aid understanding of irAE development, perhaps providing the basis for a new model prospectively testing these markers to risk stratify pts receiving ICIs.

scholarly journals C reactive protein impairs adaptive immunity in immune cells of patients with melanoma

2020 ◽  
Vol 8 (1) ◽  
pp. e000234
Author(s):  
Tatsuya Yoshida ◽  
Junya Ichikawa ◽  
Iulia Giuroiu ◽  
Andressa S Laino ◽  
Yuhan Hao ◽  
...  
Keyword(s):  
T Cells ◽  
Adaptive Immunity ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Dependent Manner ◽  
C Reactive Protein ◽  
Reactive Protein ◽  
Link Type ◽  
Serum Crp

BackgroundHigh C reactive protein (CRP) levels have been reported to be associated with a poor clinical outcome in a number of malignancies and with programmed cell death protein 1 immune checkpoint blockade in patients with advanced cancer. Little is known about the direct effects of CRP on adaptive immunity in cancer. Therefore, we investigated how CRP impacted the function of T cells and dendritic cells (DCs) from patients with melanoma.MethodsThe effects of CRP on proliferation, function, gene expression and phenotype of patient T cells and DCs, and expansion of MART-1 antigen-specific T cells were analyzed by multicolor flow cytometry and RNA-seq. Additionally, serum CRP levels at baseline from patients with metastatic melanoma treated on the Checkmate-064 clinical trial were assessed by a Luminex assay.ResultsIn vitro, CRP inhibited proliferation, activation-associated phenotypes and the effector function of activated CD4+ and CD8+ T cells from patients with melanoma. CRP-treated T cells expressed high levels of interleukin-1β, which is known to enhance CRP production from the liver. CRP also suppressed formation of the immune synapse and inhibited early events in T-cell receptor engagement. In addition, CRP downregulated the expression of costimulatory molecules on mature DCs and suppressed expansion of MART-1-specific CD8+ T cells in a dose-dependent manner by impacting on both T cells and antigen-presenting cells. High-serum CRP levels at baseline were significantly associated with a shorter survival in both nivolumab-treated and ipilimumab-treated patients.ConclusionsThese findings suggest that high levels of CRP induce an immunosuppressivemilieuin melanoma and support the blockade of CRP as a therapeutic strategy to enhance immune checkpoint therapies in cancer.Trial registration numberNCT01783938andNCT02983006.

375 Expansion of HPV-16 specific T cells in patients with HPV-related cancers treated with bintrafusp alfa

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A400-A400
Author(s):  
Nicole Toney ◽  
Yo-Ting Tsai ◽  
Claire Rumfield ◽  
Samuel Pellom ◽  
Caroline Jochems ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mouse Model ◽  
Therapeutic Vaccine ◽  
T Cell Responses ◽  
Open Label ◽  
Hpv 16 ◽  
Cell Responses ◽  
Link Type ◽  
Anti Tumor Activity

BackgroundThe safety and efficacy of bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor (a TGF-β ‘trap’) fused to a human IgG1 mAb blocking PD-L1, have been demonstrated in patients with human papillomavirus (HPV)-related cancers in an open label, multicenter phase 1 trial (NCT02517398), and an open-label, single center phase 2 trial (NCT03427411). The current study aimed to investigate whether HPV-16-specific T cells are expanded with therapy and associate with the clinical response of patients in these trials. We also present pre-clinical evidence from a mouse model of HPV-associated cancer supporting the combination of bintrafusp alfa with an HPV-16 targeted therapeutic vaccine and an immunostimulatory cytokine.MethodsPeripheral blood mononuclear cells (PBMC) were obtained from 33 patients prior to and 2 weeks after 1 and/or 3 cycles of bintrafusp alfa and evaluated for HPV-16 specific CD4+ and CD8+ T cells. PBMCs were stimulated with 15-mer peptide pools of the HPV-16 E6 and E7 oncoproteins, and T cell responses were assessed for the production of cytokines (TNFa, IFNg, IL-2) and positivity for the degranulation marker CD107a. Multifunctional T cells, positive for >2 measures, were also enumerated. For pre-clinical studies, a syngeneic mouse model of TC-1 carcinoma was treated with bintrafusp alfa alone or in combination with a liposomal-based HPV-16 therapeutic vaccine (PDS 0101) and a tumor targeting immunocytokine (NHS-muIL12) and evaluated for anti-tumor activity and immune responses.ResultsHPV-16 specific T cells were increased after 1 cycle of bintrafusp alfa in a greater proportion of responders (9/14) than non-responders (4/17) (p=0.03). In addition, the magnitude of HPV-16 specific T cells was greater after 1 (p=0.04) and 3 (p<0.0001) cycles of bintrafusp alfa in responders than non-responders. Multifunctional HPV-16-specific T cells were also increased to a greater extent in responders than non-responders. Preclinical studies demonstrated that the combination of bintrafusp alfa with an HPV-16-targeted therapeutic vaccine along with an immunocytokine resulted in maximal anti-tumor activity and T cell responses.ConclusionsAn early increase in HPV-16 specific T cells (after a single administration of bintrafusp alfa, prior to restaging) was associated with clinical activity in patients with HPV-related cancers undergoing bintrafusp alfa therapy. This evidence, and the pre-clinical finding of enhanced antitumor activity observed when combining bintrafusp alfa with an HPV-16 targeted vaccine and an immunostimulatory cytokine have provided the rational for an ongoing study evaluating this combination in patients with advanced HPV-associated malignancies (NCT04287868).Ethics ApprovalAll patients provided written informed consent for participation in a clinical trial that was approved by the Institutional Review Board at the National Cancer Institute (NCT02517398, NCT03427411)

296 Immune correlates of clinical response to Avelumab in patients with advanced thymic epithelial tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A323-A323
Author(s):  
Yo-Ting Tsai ◽  
Arun Rajan ◽  
James Gulley ◽  
Jeffrey Schlom ◽  
Renee Donahue
Keyword(s):  
Clinical Response ◽  
Mononuclear Cells ◽  
Predictive Biomarkers ◽  
Lymphocytic Infiltration ◽  
Peripheral Blood Mononuclear ◽  
Thymic Epithelial Tumors ◽  
Link Type ◽  
Epithelial Tumors ◽  
Immune Correlates ◽  
Tcr Diversity

BackgroundThymic epithelial tumors (TET), consisting of thymomas and thymic carcinomas, are PD-L1-expressing tumors characterized by varying degrees of lymphocytic infiltration and a predisposition towards the development of paraneoplastic autoimmunity. As part of a phase I study (NCT01772004), the anti-tumor activity of patients with relapsed, advanced TET to avelumab (anti-PD-L1), was demonstrated and was accompanied by a high frequency of immune related adverse events (irAE). The current study aimed to identify immune related signatures that associate with clinical response and/or the development of irAE.MethodsEight patients with recurrent TET were treated with avelumab at doses of 10 mg/kg to 20 mg/kg every 2 weeks until disease progression or development of intolerable side effects. Peripheral blood mononuclear cells (PBMC) were obtained before and during therapy, and interrogated by multicolor flow cytometry to evaluate 123 immune subsets, as well as by T-cell receptor (TCR) sequencing to evaluate TCR diversity.ResultsFour of 8 TET patients had partial responses and 3 had stable disease. All responders developed irAEs that resolved with immunosuppressive therapy, compared to only 1 of 4 non responders. Analyses of PBMC subsets prior to therapy showed that responders had higher absolute lymphocyte counts, and lower frequencies of B cells, Tregs, conventional dendritic cells (cDCs), and NK cells, compared to non-responders. There was also a trend towards a higher level of TCR diversity in those patients who subsequently had a radiological response and developed irAE.ConclusionsImmune profiling identified specific immune measures prior to therapy that differed between responders and non-responders, that may serve as predictive biomarkers to identify patients with relapsed TET most likely to benefit from avelumab and/or to develop irAE.Trial RegistrationNCT01772004Ethics ApprovalAll patients provided written informed consent for participation in a clinical trial that was approved by the Institutional Review Board at the National Cancer Institute (NCT01772004).

scholarly journals Inhibition of the PI3K/mTOR Pathway in Breast Cancer to Enhance Response to Immune Checkpoint Inhibitors in Breast Cancer

2021 ◽  
Vol 22 (10) ◽  
pp. 5207
Author(s):  
Chi Yan ◽  
Jinming Yang ◽  
Nabil Saleh ◽  
Sheau-Chiann Chen ◽  
Gregory D. Ayers ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Tumor Growth ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Mtor Pathway ◽  
Complete Regression ◽  
Mtor Inhibition

Objectives: Inhibition of the PI3K/mTOR pathway suppresses breast cancer (BC) growth, enhances anti-tumor immune responses, and works synergistically with immune checkpoint inhibitors (ICI). The objective here was to identify a subclass of PI3K inhibitors that, when combined with paclitaxel, is effective in enhancing response to ICI. Methods: C57BL/6 mice were orthotopically implanted with syngeneic luminal/triple-negative-like PyMT cells exhibiting high endogenous PI3K activity. Tumor growth in response to treatment with anti-PD-1 + anti-CTLA-4 (ICI), paclitaxel (PTX), and either the PI3Kα-specific inhibitor alpelisib, the pan-PI3K inhibitor copanlisib, or the broad spectrum PI3K/mTOR inhibitor gedatolisib was evaluated in reference to monotherapy or combinations of these therapies. Effects of these therapeutics on intratumoral immune populations were determined by multicolor FACS. Results: Treatment with alpelisib + PTX inhibited PyMT tumor growth and increased tumor-infiltrating granulocytes but did not significantly affect the number of tumor-infiltrating CD8+ T cells and did not synergize with ICI. Copanlisib + PTX + ICI significantly inhibited PyMT growth and increased activation of intratumoral CD8+ T cells as compared to ICI alone, yet did not inhibit tumor growth more than ICI alone. In contrast, gedatolisib + ICI resulted in significantly greater inhibition of tumor growth compared to ICI alone and induced durable dendritic-cell, CD8+ T-cell, and NK-cell responses. Adding PTX to this regimen yielded complete regression in 60% of tumors. Conclusion: PI3K/mTOR inhibition plus PTX heightens response to ICI and may provide a viable therapeutic approach for treatment of metastatic BC.

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