CTIM-22. NIVOLUMAB AND BEVACIZUMAB FOR RECURRENT GLIOBLASTOMA; T-CELL REACTIVITY AGAINST AUTOLOGOUS TUMOR CELLS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi54-vi55
Author(s):  
Simone Maarup ◽  
Signe Skadborg ◽  
Annie Borch ◽  
Arianna Draghi ◽  
Benedikte Hasselbalch ◽  
...  
Keyword(s):  
Intracellular Cytokine Staining ◽  
Tumor Infiltrating Lymphocytes ◽  
Recurrent Glioblastoma ◽  
Autologous Tumor ◽  
Open Label ◽  
Cell Reactivity ◽  
Translational Study ◽  
Novel Treatments ◽  
Before And After

Abstract INTRODUCTION Glioblastoma is an aggressive brain tumor with a median survival of 14.6 months. We have no standard treatment for relapse and known options have limited effect. Novel treatments are necessary to improve survival and quality of life. METHODS We present our trial; phase II open label, two-armed translational study of Nivolumab and Bevacizumab for recurrent GBM, who have failed Stupp’s regimen. Patients are included in two arms depending on the possibility of salvage neurosurgical resection. Both arms receive Nivolumab and Bevacizumab administrated every second weekend, and the surgical arm also receive Nivolumab 7 days prior surgery. Forty-four patients were included by January 2021; 20 in each arm (four screen-failures). In the surgical arm, 20 fresh tumor samples as well as paired tissue from primary tumor were available. Tumor infiltrating lymphocytes (TILs) and tumor digest were produced in vitro from recurrent settings. Young TILs were expanded from fresh tumor fragments after minimal-culture, whereas rapidly expanded TILs (REP TILs) were obtained after massive expansion. By intracellular cytokine staining, we investigated the TIL reactivity after exposure to autologous tumor digest in order to evaluate whether the TILs were tumor-reactive, non-reactive or bystanders. RNA and whole exome sequencing were available before and after treatment. RESULTS Material from 19 patients was analyzed (one out of the 20 collected biopsies was limited in size, therefore no tumor digest could be produced). Four out of 19 TIL samples showed tumor reactivity after exposure to the autologous tumor digest. Tumor reactivity was ranged between 1,2 to 13,6 tox% in CD8+ TILs and between 2,8 to 10,9 tox% in CD4+ TILs. By flowcytometry we found, IgG4+ CD3+ TILS from tumor biopsies, meaning that Nivolumab were found in the brain. Currently controls are included to evaluate these results. CONCLUSIONS Updated results will be presented at SNO.

scholarly journals ATIM-01. NIVOLUMAB AND BEVACIZUMAB FOR RECURRENT GLIOBLASTOMA; A TRANSLATIONAL TRIAL IN PROGRESS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi1-vi1
Author(s):  
Simone Eibye ◽  
Benedikte Hasselbalch ◽  
Inge Marie Svane ◽  
Sine Reker Hadrup ◽  
Lars Rønn Olsen ◽  
...  
Keyword(s):  
Tumor Infiltrating Lymphocytes ◽  
Standard Of Care ◽  
Primary Objective ◽  
Recurrent Glioblastoma ◽  
Sequencing Data ◽  
Full Genome Sequencing ◽  
Open Label ◽  
Blood Samples ◽  
Translational Study ◽  
The Impact

Abstract Glioblastoma multiforme (GBM) is an aggressive brain tumor with a poor prognosis. Standard of care at diagnosis is surgical resection, followed by radiation and temozolomide. Receiving this therapy, the median survival is 14.6 months [1]. We have no standard treatment for relapse and known options have limited effect. There is an urgent need for novel treatment interventions to improve clinical outcomes and quality of life. Recently, improved overall survival has been achieved with immune therapeutics in melanoma and renal cell carcinoma. Accordingly, it has been posited that immunotherapy may offer promise in other difficult cancers such as GBM [2]. We present our translational study; a phase II open label, two-armed translational study of Nivolumab and Bevacizumab for recurrent GBM, who have failed Stupp’s regime [1]. Patients are included in two arms depending on possibly salvage neurosurgical resection. Both arms receive Nivolumab and Bevacizumab administrated every second weekend, but the surgical arm also receive Nivolumab 7 days prior surgery. We expect 40 patients; 20 in each arm. Enrollment period is expected to 20 months, started October 2018. Our primary objective is to make preliminary assessment of immune related biomarkers, including PD-L1; therefore, we perform full genome sequencing on tumor biopsies from the surgical arm and on blood samples from both arms. We evaluate changes in the transcriptomic landscape caused by the check-point inhibition and relation to response as compared with baseline sequencing data, as well as the impact of tumor mutation burden and neoepitope load. We investigate the tumor microenvironment by harvesting tumor infiltrating lymphocytes and study the composition by flow-cytometry. The patients are evaluated by blood samples, FET-PET as wells as clinical examinations to evaluate PFS and OS. Overall the study will provide us with a unique possibility to investigate and thereof predict which patients will profit from the treatment.

EXTH-48. NOVEL COMBINATION THERAPY IN PRECLINICAL GLIOMA MODELS USING THE CELL CYCLE STABILIZING COMPOUND ARGYRIN F AND CHECKPOINT INHIBITION

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi174-vi174
Author(s):  
Bianca Walter ◽  
Denis Canjuga ◽  
Simge G Yuez ◽  
Michael Ghosh ◽  
Przemyslaw Bozko ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Ex Vivo ◽  
Tumor Infiltrating Lymphocytes ◽  
Clonogenic Survival ◽  
Autologous Tumor ◽  
Cycle Arrest ◽  
Resected Tissue ◽  
Infiltrating Lymphocytes

Abstract Glioblastoma are incurable aggressive tumors and remain a therapeutic challenge. Glioblastoma frequently harbor alterations in the retinoblastoma pathway with subsequent cell cycle abnormalities. Here, we aimed to investigate the anti-glioma activity of the cell cycle-stabilizing compound Argyrin F and its potential treatment-induced vulnerabilities to exploit possibilities for novel combination therapies. We investigated cell viability, clonogenic survival, cell cycle status and immunoblots of human and murine glioma cells treated with Argyrin F. Moreover, we established an ex vivo glioma model using residual freshly resected tissue from patients, i.e. patient-derived microtumors (PDMs). Additionally, we extracted autologous tumor infiltrating lymphocytes (TILs) to perform co-culturing experiments. We performed mass spectrometry-based immunopeptidomics and used the orthotopic syngeneic SMA560/VM/Dk glioma mouse model. Argyrin F displayed anti-glioma efficacy in glioma cell lines in vitro and in PDM models ex vivo. Moreover, Argyrin F treatment induced cell cycle arrest, reduced clonogenic survival in vitro and prolonged survival in vivo. Argyrin F-treated SMA560 glioma displayed 4.6-fold more glioma-infiltrating CD8+ T cells. We discovered a distinctive treatment-induced immunopeptidome. Combination of Argyrin F plus PD-1 antibody increased cellular toxicity in PDM/TILs co-cultures ex vivo and prolonged overall survival compared with monotherapies in vivo. We conclude that our experimental data suggest a novel combination of Argyrin F plus PD-1 blockade and its clinical translation.

Study assessing the efficacy of herbal teas on bone health and quality of life in a population with osteopenia: rooibos actions on melatonin and tulsi actions on quality of life.

2021 ◽  
Vol 4 (2) ◽  
pp. 270-298
Author(s):  
Fahima Munmun ◽  
Alyssa Linden ◽  
Hunter Hanlon ◽  
Hannah Enderby ◽  
Paula Witt-Enderby
Keyword(s):  
Quality Of Life ◽  
Oxidative Stress ◽  
Bone Health ◽  
Human Mesenchymal Stem Cell ◽  
Melatonin Receptors ◽  
Cooperative Effort ◽  
Translational Study ◽  
Before And After

The purpose of the OsTea translational study was to assess the efficacy of teas (tulsi, rooibos, oolong) compared to placebo (coriander) on markers of bone health and quality of life (QOL) in those with osteopenia and on human mesenchymal stem cell (hMSC) differentiation into osteoblasts to identify potential mechanisms of action. Following consumption of tea (3 times/day; 90 days), participants collected a urine sample during the night (10pm-6am) and filled in questionnaires before and after the study. Rooibos consumption demonstrated a significant decrease in urinary CTX levels vs placebo; trended towards increases in nocturnal melatonin levels (p=0.06); significantly decreased serotonin-producing microbes in the gut; and demonstrated trends towards improvements (p=0.09) in QUALIOST emotional parameters. Tulsi consumption primarily affected subjective measures, such as significantly improved scores for PSS, STAI-trait anxiety, and osteoporosis/osteopenia-related parameters in the QUALIOST. To further identify potential mechanisms underlying these actions of rooibos on CTX and melatonin (urinary and gut), rooibos and melatonin effects on human osteoblastogenesis were carried out for 21 days under oxidative stress conditions to mimic osteopenia.  Although both rooibos and melatonin protected against oxidative stress-induced loss of osteoblasts in vitro, their underlying mechanisms were different.  Melatonin, like tulsi and oolong, demonstrated the greatest protection against oxidative stress at days 10-11 of exposure, which was due to effects on hMSC viability and through melatonin receptors. Rooibos, on the other hand, demonstrated protection at days 10-11 and 20-21, which was through signaling mechanisms involved in differentiation processes and not on cell viability. These findings suggest that the clinical actions of rooibos on decreasing CTX levels in a population with osteopenia may be through a cooperative effort between melatonin and rooibos by protecting hMSC viability against oxidative stress-induced loss and by promoting osteoblast differentiation, respectively.  This study also supports the use of tulsi for improving quality of life in a population susceptible to osteoporosis.

scholarly journals Qualitative Analysis of Tumor-Infiltrating Lymphocytes across Human Tumor Types Reveals a Higher Proportion of Bystander CD8+ T Cells in Non-Melanoma Cancers Compared to Melanoma

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3344
Author(s):  
Aishwarya Gokuldass ◽  
Arianna Draghi ◽  
Krisztian Papp ◽  
Troels Holz Borch ◽  
Morten Nielsen ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
T Cells ◽  
T Cell ◽  
Tumor Infiltrating Lymphocytes ◽  
Autologous Tumor ◽  
Epithelial Cancers ◽  
Single Cell Rna Sequencing ◽  
Tumor Types ◽  
Infiltrating Lymphocytes

Background: Human intratumoral T cell infiltrates can be defined by quantitative or qualitative features, such as their ability to recognize autologous tumor antigens. In this study, we reproduced the tumor-T cell interactions of individual patients to determine and compared the qualitative characteristics of intratumoral T cell infiltrates across multiple tumor types. Methods: We employed 187 pairs of unselected tumor-infiltrating lymphocytes (TILs) and autologous tumor cells from patients with melanoma, renal-, ovarian-cancer or sarcoma, and single-cell RNA sequencing data from a pooled cohort of 93 patients with melanoma or epithelial cancers. Measures of TIL quality including the proportion of tumor-reactive CD8+ and CD4+ TILs, and TIL response polyfunctionality were determined. Results: Tumor-specific CD8+ and CD4+ TIL responses were detected in over half of the patients in vitro, and greater CD8+ TIL responses were observed in melanoma, regardless of previous anti-PD-1 treatment, compared to renal cancer, ovarian cancer and sarcoma. The proportion of tumor-reactive CD4+ TILs was on average lower and the differences less pronounced across tumor types. Overall, the proportion of tumor-reactive TILs in vitro was remarkably low, implying a high fraction of TILs to be bystanders, and highly variable within the same tumor type. In situ analyses, based on eight single-cell RNA-sequencing datasets encompassing melanoma and five epithelial cancers types, corroborated the results obtained in vitro. Strikingly, no strong correlation between the proportion of CD8+ and CD4+ tumor-reactive TILs was detected, suggesting the accumulation of these responses in the tumor microenvironment to follow non-overlapping biological pathways. Additionally, no strong correlation between TIL responses and tumor mutational burden (TMB) in melanoma was observed, indicating that TMB was not a major driving force of response. No substantial differences in polyfunctionality across tumor types were observed. Conclusions: These analyses shed light on the functional features defining the quality of TIL infiltrates in cancer. A significant proportion of TILs across tumor types, especially non-melanoma, are bystander T cells. These results highlight the need to develop strategies focused on the tumor-reactive TIL subpopulation.

scholarly journals Ibrexafungerp: A Novel Oral Triterpenoid Antifungal in Development for the Treatment of Candida auris Infections

Antibiotics ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 539
Author(s):  
Mahmoud Ghannoum ◽  
Maiken Cavling Arendrup ◽  
Vishnu P. Chaturvedi ◽  
Shawn R. Lockhart ◽  
Thomas S. McCormick ◽  
...  
Keyword(s):  
Antifungal Agent ◽  
Complete Response ◽  
Clinical Results ◽  
Multidrug Resistant ◽  
Candida Auris ◽  
Open Label ◽  
Candida Spp ◽  
Fungal Cell ◽  
Novel Treatments

Candida auris is an emerging multidrug-resistant fungal pathogen reported worldwide. Infections due to C. auris are usually nosocomial and associated with high rates of fluconazole resistance and mortality. Echinocandins are utilized as the first-line treatment. However, echinocandins are only available intravenously and are associated with increasingly higher rates of resistance by C. auris. Thus, a need exists for novel treatments that demonstrate potent activity against C. auris. Ibrexafungerp is a first-in-class triterpenoid antifungal agent. Similar to echinocandins, ibrexafungerp inhibits (1→3)-β-D-glucan synthase, a key component of the fungal cell wall, resulting in fungicidal activity against Candida spp. Ibrexafungerp demonstrates broad in vitro activity against various Candida spp. including C. auris and C. auris isolates with fks mutations. Minimum inhibitory concentration (MIC50 and MIC90) values in >400 C. auris isolates were 0.5 μg/mL and 1.0 μg/mL, respectively. Clinical results were reported for two patients with invasive candidiasis or candidemia due to C. auris treated during the CARES (Candidiasis Caused by Candida Auris) trial, an ongoing open-label study. These patients experienced a complete response after treatment with ibrexafungerp. Thus, ibrexafungerp represents a promising new antifungal agent for treating C. auris infections.

BBI608-201GBM: A phase Ib/II clinical study of napabucasin (BBI608) in combination with temozolomide (TMZ) for adult patients with recurrent glioblastoma (GBM).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e13525-e13525 ◽  
Author(s):  
Warren P. Mason ◽  
Paula de Robles ◽  
Laura Borodyansky ◽  
Matthew Hitron ◽  
Waldo Feliu Ortuzar ◽  
...  
Keyword(s):  
Recurrent Glioblastoma ◽  
Open Label ◽  
Cancer Stemness ◽  
Phase Ib ◽  
Anti Cancer ◽  
First Recurrence ◽  
Multi Center Study ◽  
Anti Tumor Activity

e13525 Background: Napabucasin, a first-in-class cancer stemness inhibitor in clinical development, suppresses cancer stemness by targeting STAT3-driven gene transcription. Pre-clinically, potent and broad-spectrum anti-cancer activity was observed in vitro and in vivo, alone and in combination with other agents. PK studies demonstrated napabucasin penetration in the murine orthotopic GBM model. Methods: A phase Ib/II open-label, multi-center study in pts with GBM at first recurrence who have not received bevacizumab, was performed to determine safety and preliminary activity of napabucasin administered orally at 480mg BID po in combination with TMZ 150mg/m²/day po; days 1 through 5 of each 28 day cycle, until disease progression or unacceptable toxicity. A 6-patient safety cohort was planned to evaluate the occurrence of DLT during the first 28 days of combination treatment with napabucasin and TMZ. 4 additional patients have been enrolled under the RP2D expansion phase. Results: 11 pts have been enrolled to date; no DLT was observed in the safety cohort and the RP2D of the combination is 480 mg BID for napabucasin. The safety profile was consistent with that of each agent as monotherapy and most common AEs included grade 1/2 diarrhea, nausea, abdominal cramps, and vomiting. Two patients requested to withdraw treatment due to concurrent conditions and AE s. 9 patients were evaluable by RANO; Disease Control Rate was observed in 5 patients (55.5%) of which 4 achieved PR (44.4%) and 1 achieved SD (11.1%). The Overall response rate was 44.4% in the evaluable patients. Conclusions: This phase Ib/II study demonstrated that napabucasin at 480 mg BID can be safely combined with temozolomide at full dose and showed encouraging anti-tumor activity in patients with recurrent Glioblastoma. Clinical trial information: NCT02315534. [Table: see text]

Generation and characterization of antitumor infiltrating lymphocytes from patients with breast cancer for adoptive cell transfer therapy.

2017 ◽  
Vol 35 (7_suppl) ◽  
pp. 145-145
Author(s):  
Juhua Zhou ◽  
Yin Zhong ◽  
Zhongjun Hou ◽  
Jianzhong Zhang ◽  
Yanmin Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Tumor Cells ◽  
Tumor Infiltrating Lymphocytes ◽  
Adoptive Cell Transfer ◽  
Autologous Tumor ◽  
Cell Transfer ◽  
Adoptive Cell Transfer Therapy ◽  
Infiltrating Lymphocytes

145 Background: Clinical trials have shown that adoptive cell transfer therapy is a promising method for cancer treatment. In the current study, we aim to generate and characterize anti-tumor tumor-infiltrating lymphocytes from patients with breast cancer for adoptive cell transfer therapy. Methods: In vitro culture method was used to generate anti-tumor, tumor-infiltrating lymphocytes from patients with breast cancer. FACS analysis, ELISA, and Elispot assay were used to characterize tumor-infiltrating lymphocytes. Autologous anti-tumor tumor-infiltrating lymphocytes from patients with breast cancer were used in adoptive cell transfer therapy. Results: FACS analysis indicated that tumor-infiltrating lymphocytes were present in the tumor tissues, but not detectable in the normal breast tissues from patients with breast cancer. Tumor-infiltrating lymphocytes could be generated in vitro from fresh tumor specimens of patients with breast cancer. Both CD4 T cells and CD8 T cells were detected in tumor-infiltrating lymphocytes. Autologous tumor cells could also generate in vitro from fresh tumor tissue samples of patients with breast cancer. Among 22 samples screened, 6 samples (25%) of tumor-infiltrating lymphocytes are tumor-reactive. Anti-tumor, tumor-infiltrating lymphocytes could recognize autologous tumor cells and allogenic tumor cells. After a large scale T cell expansion, anti-tumor reactivity was maintained in tumor-infiltrating lymphocytes. All of tumor-infiltrating lymphocytes were NK cells in some samples from patients with breast cancer, and these NK cells could recognize autologous tumor cells and a panel of allogenic tumor cells. T cell cloning assay demonstrated that some of the tumor-reactive, tumor-infiltrating lymphocytes were CD4 T cells. Conclusions: The results suggest that anti-tumor, tumor-infiltrating lymphocytes may be generated from patients with breast cancer, which may be used in clinical applications of adoptive cell transfer therapy for patients with breast cancer. The clinical trial of adoptive cell transfer therapy using autologous anti-tumor tumor-infiltrating lymphocytes for patients with breast is under way.

scholarly journals Rapid Identification of the Tumor-Specific Reactive TIL Repertoire via Combined Detection of CD137, TNF, and IFNγ, Following Recognition of Autologous Tumor-Antigens

2021 ◽  
Vol 12 ◽  
Author(s):  
Arianna Draghi ◽  
Christopher Aled Chamberlain ◽  
Shawez Khan ◽  
Krisztian Papp ◽  
Martin Lauss ◽  
...  
Keyword(s):  
Tumor Antigens ◽  
De Novo ◽  
Tumor Infiltrating Lymphocytes ◽  
Rapid Identification ◽  
Autologous Tumor ◽  
Simple Method ◽  
Straightforward Method ◽  
Infiltrating Lymphocytes ◽  
Combined Detection

Detecting the entire repertoire of tumor-specific reactive tumor-infiltrating lymphocytes (TILs) is essential for investigating their immunological functions in the tumor microenvironment. Current in vitro assays identifying tumor-specific functional activation measure the upregulation of surface molecules, de novo production of antitumor cytokines, or mobilization of cytotoxic granules following recognition of tumor-antigens, yet there is no widely adopted standard method. Here we established an enhanced, yet simple, method for identifying simultaneously CD8+ and CD4+ tumor-specific reactive TILs in vitro, using a combination of widely known and available flow cytometry assays. By combining the detection of intracellular CD137 and de novo production of TNF and IFNγ after recognition of naturally-presented tumor antigens, we demonstrate that a larger fraction of tumor-specific and reactive CD8+ TILs can be detected in vitro compared to commonly used assays. This assay revealed multiple polyfunctionality-based clusters of both CD4+ and CD8+ tumor-specific reactive TILs. In situ, the combined detection of TNFRSF9, TNF, and IFNG identified most of the tumor-specific reactive TIL repertoire. In conclusion, we describe a straightforward method for efficient identification of the tumor-specific reactive TIL repertoire in vitro, which can be rapidly adopted in most cancer immunology laboratories.

Evaluating the antitumor role of B cells in patients with non-small cell lung cancer.

2017 ◽  
Vol 35 (7_suppl) ◽  
pp. 75-75 ◽  
Author(s):  
Tullia C. Bruno
Keyword(s):  
B Cells ◽  
Antigen Presentation ◽  
T Regulatory Cells ◽  
Tumor Antigens ◽  
Nsclc Patient ◽  
Tumor Infiltrating Lymphocytes ◽  
Autologous Tumor ◽  
Adjacent Tissue ◽  
Nsclc Patients

75 Background: The focus of immunotherapy has been on CD8 and CD4 tumor infiltrating lymphocytes (TILs), however, tumor infiltrating B cells (TIL-Bs) have been reported in tertiary lymphoid structures (TLS) with CD4 TILs, and both TIL-Bs and TLS correlate with NSCLC patient survival. While TIL-Bs have been identified in NSCLC patients, their function in the tumor microenvironment has been understudied with no focus on their role as antigen presenting cells (APCs) and their influence on CD8 and CD4 TILs. We hypothesize that TIL-Bs help generate potent, long-term immune responses against cancer by presenting tumor antigens to CD4 TILs. Methods: We used freshly isolated B cells from NSCLC patient tumor and tumor adjacent tissue to determine TIL-B function. We generated a specific in vitro antigen presentation assay to determine APC function and immunoregulation by TIL-Bs, and we correlated our findings with tumor-free survival. Results: We observed that the total number of B cells at the site of the tumor versus the tumor-adjacent tissue was increased compared to other immune subsets. Further, we observed three types of CD4 TIL responses when TIL-Bs presented autologous tumor antigens. There were activated responder CD4 TILs that proliferated when combined with TIL-Bs alone, which indicates stimulation with endogenous tumor antigens. There were antigen-associated responders that required exogenous autologous tumor lysate to elicit a CD4 TIL response, and there were patient CD4 TILs that did not respond to antigen presentation by TIL-Bs. Within the activated and antigen-associated responders, the TIL-B phenotype influenced the CD4 TIL phenotype; if the TIL-Bs were activated (CD69+CD27+CD21+), the CD4 TILs were T helper (anti-tumor) CD4 T cells and if the TIL-Bs were exhausted (CD69-CD27-CD21-), the CD4 TILs were T regulatory cells (pro-tumor). These data suggest that TIL-Bs influence the phenotype and function of CD4 TILs in NSCLC patient tumors. Conclusions: In conclusion, determining if TIL-Bs are activated or exhausted in NSCLC patients will determine the extent of their anti-tumor function in cancer. Ultimately, results from this study will help predict how to target TIL-B functions in future immunotherapies for NSCLC patients.

TAS-116, an oral HSP90 inhibitor, in combination with nivolumab in patients with colorectal cancer and other solid tumors: An open-label, dose-finding, and expansion phase Ib trial (EPOC1704).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 4044-4044 ◽  
Author(s):  
Akihito Kawazoe ◽  
Noboru Yamamoto ◽  
Daisuke Kotani ◽  
Yasutoshi Kuboki ◽  
Hiroya Taniguchi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Solid Tumors ◽  
Objective Response ◽  
Tumor Infiltrating Lymphocytes ◽  
Maximum Tolerated Dose ◽  
Hsp90 Inhibitor ◽  
Dose Finding ◽  
Open Label

4044 Background: Regulatory T cells (Tregs) potentially induce the resistance of anti-PD1/PD-L1 inhibitors (A-PD1). TAS-116, a novel HSP90 inhibitor, enhanced antitumor immunity via reducing Tregs in vitro and in vivo. Combination of TAS-116 plus A-PD1 showed a superior tumor growth suppression compared with either treatment alone in vivo. Based on the above, we investigated safety and efficacy of TAS-116 in combination with nivolumab in patients with solid tumors. Methods: Enrolled patients received TAS-116 plus nivolumab in a dose-finding part to estimate the maximum tolerated dose and the recommended phase 2 dose (RP2D). Additional patients were enrolled in a dose-expansion part. TAS-116 monotherapy (orally once daily, 80mg on level 1, 120mg on level 2, and 160mg on level 3) was administrated for 2 weeks followed by the combination with nivolumab (intravenously every 2 weeks, 3 mg/kg). The primary endpoint was dose-limiting toxicities (DLTs) during the first cycle (4 weeks). PD-L1 combined positive score (CPS) and tumor mutation burden (TMB) were assessed. We also conducted biomarker research using paired samples from repeated tumor biopsies and blood collections. Results: A total of 44 patients with colorectal cancer (CRC, n = 29), gastric cancer (GC, n = 8), sarcoma (n = 5), non-small cell lung cancer (NSCLC, n = 1) and melanoma (n = 1) after standard of cares were enrolled. One patient had MSI-H CRC, but all other patients had MSS tumors. No DLTs were observed at all levels and TAS-116 160 mg was determined as RP2D. The common grade 3 or worse treatment-related adverse included AST/ALT increased (7%), creatinine increased (5%) and platelet count decreased (5%). Objective tumor response was observed in 6 patients including 4 MSS CRC, 1 MSI-H CRC and 1 sarcoma, resulting in objective response rate (ORR) of 16% in MSS CRC without prior A-PD-1. PD-L1 CPS and TMB could be evaluated in 18 and 17 MSS CRC without prior A-PD-1, respectively. ORR was 27% in patients with CPS ≥1 and 0% in patients with CPS < 1. ORR was 33% with TMB-high (median as the cut-off) and 12% with TMB-low. Analysis of tumor-infiltrating lymphocytes before treatment and after TAS-116 monotherapy demonstrated reduction of FoxP3hiCD45RA−Tregs fraction in the tumor microenvironment. Conclusions: The combination of TAS-116 160mg plus nivolumab had manageable safety profiles and anti-tumor activity especially for MSS CRC patients, which warrants further investigations in a large cohort. Clinical trial information: UMIN000032801 .

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