Phase I/Ib study of pembrolizumab and vorinostat in patients with metastatic NSCLC (mNSCLC): Updated results.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9073-9073
Author(s):  
Andreas Nicholas Saltos ◽  
Tawee Tanvetyanon ◽  
Eric B. Haura ◽  
Ben C. Creelan ◽  
Scott Joseph Antonia ◽  
...  
Keyword(s):  
T Cell ◽  
Phase I ◽  
Histone Deacetylase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Suppressor Cells ◽  
Phase Ib ◽  
Primary Endpoints ◽  
Trial Testing ◽  
Tumor Immunogenicity ◽  
Blood Specimens

9073 Background: Histone deacetylase inhibitors (HDACi) enhance tumor immunogenicity through several mechanisms and may augment response to immune checkpoint inhibitors (ICI). We report updated results from a phase I/Ib trial testing the combination of oral HDACi vorinostat (V) with PD-1 inhibitor pembrolizumab (P) in mNSCLC. Methods: In phase I, pts with ICI-naïve or ICI-pretreated mNSCLC were treated with P (200mg IV q3 wk) + V (200 or 400 mg PO daily). In phase Ib expansion, pts were required to have progressed on prior ICI treatment. Primary endpoints were safety/tolerability; secondary endpoints included RR, PFS, DOR, and OS. Tissue and blood specimens from pre- and on-treatment were collected for correlative analyses to determine tumor gene expression changes, T cell density and levels of myeloid-derived suppressor cells. Results: Between 3/2016 - 12/2018, Phase I: 13 pts were treated (4 at 200mg, and 9 at 400mg V dose); and Phase Ib: 20 pts were treated. Median age: 68 (range 38-82); Females: 11 (33%); ECOG 1: 31 (94%); and never/former/current smokers: 3/22/8 (9%/67%/24%). PD-L1 expression was < 1% in 8/33 (18%), ≥1-49% in 7/33 (21%), ≥ 50% in 9/33 (27%) and unknown in 11/30 (33%). No DLTs or treatment related deaths were observed. The RP2D was P 200mg and V 400mg. Most common any grade AEs was fatigue (11%) and nausea/vomiting (8%). 2 (6%) patients had treatment discontinued due to toxicity. 30 pts are evaluable for response, 6 ICI-naïve and 24 ICI-pretreated. 4 (13%) had PR (2 confirmed), 16 (53%) had SD, and 10 (33%) had PD for a disease control rate of 67%. In the ICI-pretreated Ib cohort, 3 pts (1 confirmed; 2 unconfirmed) had a PR and 10 had SD (8 confirmed). For ICI-pretreated pts, mPFS was 3.2 and mOS was 7.3 months, and 1-year PFS was 17% (4 pts). For ICI-naïve, mPFS was 7.6 months and mOS was 16 months. CD8 T cell presence in tumor stromal regions was associated with benefit to P + V treatment. Conclusions: P + V were well tolerated. The combination demonstrates preliminary anti-tumor activity despite progression on prior ICI treatment and stromal CD8 T cells may be associated with benefit from P + V treatment. A randomized phase II portion of this study, examining P combined with V vs. placebo in immunotherapy naïve pts, is ongoing. Clinical trial information: NCT02638090.

scholarly journals Updates in Clinical Data on FDA Fast Track Drugs for Relapsed Refractory Multiple Myeloma: A Systematic Review of Literature

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5579-5579
Author(s):  
Muhammad Abdullah Yousaf ◽  
Muhaddis Ejaz Ahmad ◽  
Maaz Ahmed Yusufi ◽  
Asim Tameez ud din ◽  
Muhammad Qudrat Ullah ◽  
...  
Keyword(s):  
T Cell ◽  
Partial Response ◽  
Phase I ◽  
Phase I Study ◽  
Fast Track ◽  
Single Agent ◽  
Phase Ib ◽  
D 20 ◽  
Combination Regimens ◽  
Good Partial Response

Introduction FDA (Food and Drug Administration) fast track program facilitates the development and accelerated review of new drugs aimed at treating life-threatening conditions and having the potential to address unmet medical needs. FDA fast track drugs (2019) for relapsed refractory MM include selective exportin-1 (XPO-1) inhibitors, first generation Selinexor / KPT-330 (S) and second generation KPT-8602, and an anti-B-cell maturation antigen (BCMA) bispecific T-cell engager (BiTE), AMG-420. The aim of our study is to analyze published literature for updates in clinical data viz efficacy and toxicity of these new agents in pts with RRMM. Methods Following PRISMA guidelines, we performed a comprehensive literature search on articles published after 2014 using Pubmed, Embase, Cochrane and Web of Science. Fifty-eight articles were identified initially and after a detailed scrutiny, we finalized 8 studies involving 299 RRMM patients and summarized the data using absolute values and percentages. Chimeric antigen receptor (CAR) T-cell therapy was excluded from our manuscript. Results Selinexor / KPT-330: A total of 6 studies (Table 1) involving 258 RRMM pts were included. In a phase Ib/II study by Bahlis et al., S was given in combination with bortezomib (V) and dexamethasone (d) to 22 pts with 4 median prior lines of therapy. The overall response rate (ORR) was 77% with complete response (CR) in 5%, partial response (PR) in 50% and very good partial response (VGPR) in 23% pts. In another phase Ib/II study by the same author, SVd was given to 42 pts with 3 median prior therapies. In 40 evaluable pts, ORR was 63% with CR in 8%, PR in 33%, and VGPR in 23%. The progression free survival (PFS) was 9 months. In a phase I/II study by Broijl et al., S (45 or 30 mg/m2) was given in combination with Vd to pts with median 3 prior treatments. Among 5 evaluable pts who received 45 mg/m2 of S, PR was observed in 80% and VGPR was observed in 40% pts. OS was 100% and 75% at 12 and 24 months respectively and PFS was 17 months. In pts who received S (30 mg/m2) with Vd, PR was observed in 67% and VGPR was observed in 17% pts. OS was 75% at 12 months and PFS was 10 months. In a phase II study by Vogl et al, 79 pts received S (80 mg) in combination with d (20 mg), both orally and twice weekly. Median prior therapies received were 7. In 78 evaluable patients, the ORR was 21% with PR in 15% and VGPR in 5%. OS and PFS were 9.3 and 2.3 months respectively. In a phase I study by Chen et al., 84 pts having received 6 median prior therapies were included. S was given either alone or in combination with d. Fourteen pts were rendered ineligible for response. ORR was 4% for pts who received single-agent S and 22% for those who received S+d. PR was observed in 4% of single-agent S pts. Among S+d pts, all responses were observed in S (45 mg/m2) plus d (20 mg) group (ORR 50%) with CR in 8% and PR in 42% pts. In a phase I study by Jakobowiak et al., 18 pts with median 3 prior therapies were included. S in combination with carfilzomib (CFZ) and d were given. Among 16 evaluable patients, PR was observed in 63% and VGPR was observed in 25% pts. On July 3, 2019, FDA granted accelerated approval to selinexor. KP-8602: In a phase I/II trial by Cornell et al., involving 6 pts, KP-8602 (5 mg PO QDx5) in combination with dexamethasone (20 mg 2QWK) was given for 28 days. they had received 6 median prior lines of therapy. PR was observed in 16% of the pts. AMG-420: In a phase I study by Topp et al., 35 pts with median 4 prior lines of therapy were included. Single-agent AMG-420 (0.2-800 µg/day) was given. CR was observed in 17% pts. The highest dose at which a CR was observed was 400 µg/day. It was also the dose at which maximum number of pts showed a CR (n=3, 9%). A partial response (PR) and a very good partial response (VGPR) was also observed in 1 patient each i.e. 3%. Conclusion Combination regimens of SVd has superior efficacy as compared to S monotherapy. Major adverse events reported with both single-agent and combination regimens are hematological i.e. thrombocytopenia, neutropenia and anemia. KP-8602 has promising efficacy in limited pts and appear to have better adverse effect profile. AMG-420 has shown promising activity and tolerability in RRMM pts at a dose of 400 µg/day with no major toxicities at this dose. The published data on these drugs is scarce, still emerging and warrants further investigation. Disclosures Anwer: In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

scholarly journals From Tumor Mutational Burden to Blood T Cell Receptor: Looking for the Best Predictive Biomarker in Lung Cancer Treated with Immunotherapy

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2974
Author(s):  
Andrea Sesma ◽  
Julián Pardo ◽  
Mara Cruellas ◽  
Eva M. Gálvez ◽  
Marta Gascón ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cell ◽  
T Cell Receptor ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarker ◽  
Cell Receptor ◽  
Mutational Burden ◽  
Tcr Repertoire ◽  
Tumor Mutational Burden ◽  
Tumor Immunogenicity

Despite therapeutic advances, lung cancer (LC) is one of the leading causes of cancer morbidity and mortality worldwide. Recently, the treatment of advanced LC has experienced important changes in survival benefit due to immune checkpoint inhibitors (ICIs). However, overall response rates (ORR) remain low in unselected patients and a large proportion of patients undergo disease progression in the first weeks of treatment. Therefore, there is a need of biomarkers to identify patients who will benefit from ICIs. The programmed cell death ligand 1 (PD-L1) expression has been the first biomarker developed. However, its use as a robust predictive biomarker has been limited due to the variability of techniques used, with different antibodies and thresholds. In this context, tumor mutational burden (TMB) has emerged as an additional powerful biomarker based on the observation of successful response to ICIs in solid tumors with high TMB. TMB can be defined as the total number of nonsynonymous mutations per DNA megabases being a mechanism generating neoantigens conditioning the tumor immunogenicity and response to ICIs. However, the latest data provide conflicting results regarding its role as a biomarker. Moreover, considering the results of the recent data, the use of peripheral blood T cell receptor (TCR) repertoire could be a new predictive biomarker. This review summarises recent findings describing the clinical utility of TMB and TCRβ (TCRB) and concludes that immune, neontigen, and checkpoint targeted variables are required in combination for accurately identifying patients who most likely will benefit of ICIs.

Function and expression of checkpoint inhibitors and immune agonists on immune cells in monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM) and MM and tumor-specific T lymphocytes.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 11577-11577 ◽  
Author(s):  
Jooeun Bae ◽  
Brandon Nguyen ◽  
Yu-Tzu Tai ◽  
Teru Hideshima ◽  
Dharminder Chauhan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Suppressor Cells ◽  
Treg Cells ◽  
T Cell Subsets ◽  
Direct Stimulation ◽  
Novel Therapeutic Strategies

11577 Background: Characterization of expression and function of immune regulatory molecules in tumor microenvironment will provide the framework for developing novel therapeutic strategies. Methods: We evaluated the expression and functional impact of various immuno-regulatory molecules, PD-1, PDL-1, PDL-2, LAG3, TIM3, OX40 and GITR, on the CD138+ tumor cells, myeloid derived suppressor cells (MDSC), and T cell subsets from patients with MGUS, SMM and active MM (newly diagnosed, relapsed, relapsed/refractory), and the myeloma-specific cytotoxic T lymphocytes (CTL) induced with XBP1/CD138/CS1 peptides. Results: PDL-1/PDL-2 was more highly expressed on CD138+ myeloma cells in active MM than SMM or MGUS. G-type MDSC (CD11b+CD33+HLA-DRlowCD15+). Treg cells (CD3+CD4+/CD25+FOXP3+) numbers were increased and expressed higher levels of PD1/PD-L1 in active MM than in MGUS, SMM or healthy donors. Among the checkpoint molecules (PD-1, PDL-1, PDL-2, LAG3, OX40, GITR) evaluated, PD-1 showed the highest expression on CD3+CD4+ and CD3+CD8+T cells in BMMC and PBMC from patients with active MM. Functionally, T cells from MM patients showed increased proliferation upon treatment with an individual immune agonist ( > 150%) or checkpoint inhibitor ( > 100%). Interestingly, each individual anti-checkpoint molecule induced proliferation of T cells expressing other checkpoint molecules. In addition, the blockade of PD1, LAG3 or TIM3 enhanced MM antigen-specific cytotoxicity, assessed by parameters including CD107a, granzyme B and IFN-g production, which was most prominent within the memory CTL subset of MM antigen-specific T cells. Conclusions: These results demonstrate an increased frequency of immune regulatory cells, which highly express checkpoint inhibitors in active MM. Direct stimulation with an immune agonist or blockade of a checkpoint inhibitor increased MM patients’ T cell proliferation and myeloma-specific CTL function, supporting development of combination immune regulatory therapies to improve patient outcome in MM.

scholarly journals Myeloid-Derived Suppressor Cells: Implications in the Resistance of Malignant Tumors to T Cell-Based Immunotherapy

2021 ◽  
Vol 9 ◽  
Author(s):  
Houhui Shi ◽  
Kai Li ◽  
Yanghong Ni ◽  
Xiao Liang ◽  
Xia Zhao
Keyword(s):  
T Cell ◽  
Cancer Patients ◽  
Oncolytic Virus ◽  
Malignant Tumors ◽  
Checkpoint Inhibitors ◽  
Suppressor Cells ◽  
Immunological Response ◽  
Adoptive T Cell Therapy ◽  
Myeloid Derived Suppressor Cells ◽  
T Cell Therapy

T lymphocytes function as major players in antigen-mediated cytotoxicity and have become powerful tools for exploiting the immune system in tumor elimination. Several types of T cell-based immunotherapies have been prescribed to cancer patients with durable immunological response. Such strategies include immune checkpoint inhibitors, adoptive T cell therapy, cancer vaccines, oncolytic virus, and modulatory cytokines. However, the majority of cancer patients still failed to take the advantage of these kinds of treatments. Currently, extensive attempts are being made to uncover the potential mechanism of immunotherapy resistance, and myeloid-derived suppressor cells (MDSCs) have been identified as one of vital interpretable factors. Here, we discuss the immunosuppressive mechanism of MDSCs and their contributions to failures of T cell-based immunotherapy. Additionally, we summarize combination therapies to ameliorate the efficacy of T cell-based immunotherapy.

Safety results from phase I/II study of the PI3Kβ inhibitor GSK2636771 (G) in combination with pembrolizumab (P) in patients (pts) with PD-1 refractory metastatic melanoma (MM) and PTEN loss.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e22000-e22000 ◽  
Author(s):  
Hussein Abdul-Hassan Tawbi ◽  
Weiyi Peng ◽  
Suzanne Phillips ◽  
Denai R. Milton ◽  
Rodabe Navroze Amaria ◽  
...  
Keyword(s):  
T Cell ◽  
Phase I ◽  
Dose Level ◽  
Clinical Benefit ◽  
Renal Toxicity ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Safety Data ◽  
Pten Loss ◽  
Higher Doses

e22000 Background: Checkpoint inhibitors (CPI) have improved survival and long-term disease control in 35-40% of pts with MM. Many pts derive no clinical benefit or progress after an initial response. Our group and others have shown that loss of the tumor suppressor protein PTEN occurs in multiple cancers, up to 30% of MM pts, activates the PI3K pathway, and correlates with decreased MM response rates to CPI and decreased T cell infiltrates. In PTEN-null MM preclinical models, inhibition of the PI3Kβ-subunit with GSK2636771 (G) was superior to pan-PI3K inhibitors, increased intratumoral T cell infiltration and the activity of CPI. To test our hypothesis that PI3Kβi reverses resistance to CPI, we are conducting a Phase I/II study (NCT03131908) combining G with P in PD-1 refractory pts with PTEN loss. Methods: The primary objective of Ph I portion is to determine the Maximum-Tolerated Dose (MTD) and Recommended Phase II Dose (RP2D) of G with P in PD-1 refractory pts (including melanoma, endometrial, TNBC, and prostate cancers) with PTEN loss. Pts receive P at 200mg IV q 3 wks. G starting dose level (DL1) was 300 mg PO qd for 21 days and escalated to 400 mg PO qd (DL2) using a 3+3 design. A dose level -1 (DL-1) (200 mg PO qd) was also included in the event of unacceptable toxicities at higher doses. Ph II will accrue 35 pts at the RP2D. This study is continuously monitored for toxicity and futility. The primary objectives of Ph II are safety, tolerability, and efficacy of the combination as defined by Objective Response Rate (ORR) by RECIST 1.1. Secondary Objectives include the PKs of G and PD effects in tumor tissue as measured by pathway inhibition and T cell trafficking into tumors. Results: 13 pts have been treated, 6 at the 300mg (DL1), 5 at 400mg (DL2), and 2 at 200 mg (DL-1). One DLT (grade 3 hypocalcemia) was observed at the 300mg dose. Two DLTs were observed in the 400mg cohort, one of which was AKI requiring dialysis and the other was a Gr 3 rash. Based on this experience and additional safety data from GSK regarding renal toxicity, DL-1 was declared RP2D at 200mg. 2 pts at the RP2D have passed the DLT evaluation period without toxicities. Conclusions: The combination of G and P is being explored at the RP2D of 200 mg. Renal toxicity precluded higher doses. No objective responses have been observed although 2 pts have experienced prolonged clinical benefit including a MM pt with 27% decrease in tumor burden. Through longitudinal biopsies, we aim to better understand the role PTEN loss plays when targeted in combination with CPI. Clinical trial information: NCT03131908.

scholarly journals 821 Class specific HDAC inhibition differentially affects the function of specific T cell subsets

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A871-A871
Author(s):  
Nisha Holay ◽  
Uma Giri ◽  
Carla Van Den Berg ◽  
Gail Eckhardt ◽  
Todd Triplett
Keyword(s):  
T Cells ◽  
T Cell ◽  
Histone Deacetylase Inhibitors ◽  
Cytokine Production ◽  
T Cell Subsets ◽  
Global Changes ◽  
Functional Responses ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Tumor Immunogenicity

BackgroundHistone deacetylase inhibitors (HDACi) are currently being used in the clinic to treat a variety of cancer types. Despite their wide use, the mechanism by which they exert anti-tumor effects is largely unknown. Although originally posited to abrogate tumor proliferation via regulating tumor suppressor genes, responses to monotherapies of HDACi have been shown to be dependent on an adaptive immune system and to enhance responses to immunotherapy. However, whether this mechanism is driven by enhancing tumor immunogenicity or enhancing anti-tumor immune responses is unclear. Understanding this could help identify optimal combination regimens for augmenting immunotherapies. Given the role of epigenetics in regulating T cell differentiation upon antigen encounter into discrete subsets, these studies sought to determine whether HDACi differentially impact naïve from memory T cell subsets.MethodsPBMCs from healthy donors were stimulated with either anti-CD3/anti-CD28 or PMA/Ionomycin in the presence or absence of different HDAC inhibitors (OKI-005, 250 nM; Entinostat, 5 uM; and Vorinostat, 1 uM). Cells were evaluated at different time points by flow cytometric analysis to compare responses by T cell subsets for changes in cytokine production, protein acetylation and other functional responses. Supernatant was collected in separate experiments for comprehensive cytokine bead arrays.ResultsCytokine analysis of supernatants showed clear differences in response to HDACi as while most cytokines decreased, others were either unaffected or increased. We next performed ICS with surface markers to determine if these changes in cytokine production levels were subset specific. Comparisons of naïve and memory subsets found decreased IL-2 levels was primarily attributed to loss of production by naïve T cells. Furthermore, gain of TNFa was almost completely restricted to naïve cells. The preferential responses by naïve T cells was further verified during global changes in acetylated protein levels. Lastly, we found differences between inhibitors on their effects on T cells. As these differences remained even after controlling for potency, this suggests the specificity profiles toward individual HDACs was responsible for their unique effects.ConclusionsThese studies demonstrate clear differences in the effect of HDACi on cytokine production by distinct T cell subsets. Ongoing studies are aimed at elucidating the specific HDACs responsible for regulating T cell effector functions and tumor immunogenicity when targeted. Ultimately, understanding this could help identify inhibitors with the desired specificity profile for combining with immunotherapy.

scholarly journals Therapeutic Values of Myeloid-Derived Suppressor Cells in Hepatocellular Carcinoma: Facts and Hopes

Cancers ◽  
2021 ◽  
Vol 13 (20) ◽  
pp. 5127
Author(s):  
Yijun Wang ◽  
Tongyue Zhang ◽  
Mengyu Sun ◽  
Xiaoyu Ji ◽  
Meng Xie ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cell ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Suppressor Cells ◽  
Dependent Manner ◽  
Myeloid Derived Suppressor Cells ◽  
Contributing Factors ◽  
Essential Components

One of the major challenges in hepatocellular carcinoma (HCC) treatment is drug resistance and low responsiveness to systemic therapies, partly due to insufficient T cell infiltration. Myeloid-derived suppressor cells (MDSCs) are immature marrow-derived cell populations with heterogeneity and immunosuppression characteristics and are essential components of the suppressive tumor immune microenvironment (TIME). Increasing evidence has demonstrated that MDSCs are indispensable contributing factors to HCC development in a T cell-dependent or non-dependent manner. Clinically, the frequency of MDSCs is firmly linked to HCC clinical outcomes and the effectiveness of immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs). Furthermore, MDSCs can also be used as prognostic and predictive biomarkers for patients with HCC. Therefore, treatments reprograming MDSCs may offer potential therapeutic opportunities in HCC. Here, we recapitulated the dynamic relevance of MDSCs in the initiation and development of HCC and paid special attention to the effect of MDSCs on T cells infiltration in HCC. Finally, we pointed out the potential therapeutic effect of targeting MDSCs alone or in combination, hoping to provide new insights into HCC treatment.

PrE0807: A phase Ib feasibility trial of neoadjuvant nivolumab (N) without or with lirilumab (L) in cisplatin-ineligible patients (pts) with muscle-invasive bladder cancer (MIBC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4518-4518
Author(s):  
Petros Grivas ◽  
Jun Yin ◽  
Vadim S Koshkin ◽  
Suzanne Cole ◽  
Rohit K. Jain ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Density ◽  
Checkpoint Inhibitors ◽  
Pathologic Complete Response ◽  
Neoadjuvant Treatment ◽  
Cd8 T Cell ◽  
Feasibility Trial ◽  
Significant Activity ◽  
Eligibility Criteria ◽  
Phase Ib

4518 Background: Neoadjuvant cisplatin-based chemotherapy (CT) prior to radical cystectomy (RC) improves overall survival (OS) in MIBC, but about half of pts are cisplatin-unfit or refuse it. Neoadjuvant immune checkpoint inhibitors can induce high pathologic complete response rate (ypT0N0). The combination of anti-PD-1 (N) and anti-KIR (L) is hypothesized to be safe and have significant activity based on the complementary and possibly synergistic roles in regulating adaptive and innate immune response in MIBC. Methods: This is a phase Ib multi-institutional trial in pts with localized MIBC treated with 2 neoadjuvant doses (4 weeks apart) of N alone (480 mg) in cohort 1 or N (480 mg) + L (240 mg) in cohort 2 prior to RC without adjuvant therapy (NCT03532451). Cohorts were enrolled sequentially and were not randomized. Key eligibility criteria included stage cT2-4aN0-1M0, ≥20% tumor content at TURBT and cisplatin-ineligibility (Galsky criteria) or refusal. Primary endpoint was safety manifested as rate of ≥G3 treatment related adverse events (TRAE) assessed in each cohort with CTCAE v5.0. Key secondary endpoints included the % of pts who had RC > 6 weeks after last neoadjuvant dose due to TRAE, CD8+ T cell density at RC, ypT0N0 and < ypT2N0 rates, CD8+ T cell density change between TURBT and RC, recurrence-free survival (RFS) and biomarkers in tumor tissue, blood and urine. Results: Among 43 pts enrolled (13 cohort 1, 30 cohort 2), median age was 75 (51-89), 67% were men, all had PS ECOG 0-1. Pts were cisplatin-ineligible due to impaired renal function (47%) and hearing loss (37%), while 14 % refused cisplatin. At baseline, 37 pts had cT2 stage, 2 had cN1 and 3 cNx. In cohort 1 and 2, 13 and 29 pts, respectively, completed intended neoadjuvant treatment, and 41/43 underwent RC (12/13 cohort 1, 29/30 cohort 2). One pt progressed to metastatic disease prior to RC (cohort 1) and 1 withdrew consent prior to being treated (cohort 2). Additionally, 1 patient was found to have cervical cancer at RC. Median time from last neoadjuvant dose to RC was 27 (95%CI: 24-29) days. There was no RC delayed > 6 weeks from treatment completion due to TRAE. G3 TRAEs occurred in 0% with N and 6.7% (90%CI 1.2-19.5%) in N+L (1: arthralgia, 1: gout, 2: hip pain) that all resolved. No G4/5 TRAEs occurred. Of 40 pts with MIBC and RC, ypT0N0 rates for N and N+L were 8% and 18%, while < ypT2N0 rates were 17% and 29%, respectively. Data on RFS and OS, and biomarker data were not yet mature. Conclusions: Neoadjuvant N alone and N+L combination prior to RC were safe, feasible and well tolerated in cisplatin-ineligible pts with MIBC, but ypT0N0 rates were unexpectedly low, especially with N alone. Two phase 3 trials (NCT03661320; NCT04209114) are evaluating the peri-operative role of N + chemotherapy +/- Linrodostat in cisplatin-fit and N +/- Bempeg in cisplatin unfit patients and are also assessing biomarkers. Clinical trial information: NCT03532451.

A phase I trial of a recombinant CEA yeast-based vaccine targeting CEA-expressing cancers.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 458-458 ◽  
Author(s):  
Marijo Bilusic ◽  
James L. Gulley ◽  
James W. Hodge ◽  
Kwong Tsang ◽  
Philip M. Arlen ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
T Cell ◽  
Phase I ◽  
Phase I Trial ◽  
Injection Site Reaction ◽  
Suppressor Cells ◽  
Anterior Chest Wall ◽  
Common Adverse Event ◽  
Cell Immune Response ◽  
Serum Cea

458 Background: Saccharomyces cerevisiae (yeast) has been genetically modified to express CEA protein and employed as a heat-killed immune-stimulating, vector-based vaccine. Preclinical studies have shown that yeast CEA vaccine can induce a strong CEA-specific T-cell immune response (IR) and anti-tumor activity. Methods: Patients (Pts) were enrolled in this phase I trial at 3 dose levels: 4, 16, and 40 yeast units (each unit =107 yeast particles). The vaccine was administered equally at 4 sites subcutaneously in bilateral inguinal and anterior chest wall regions. Vaccine was administered at 2 week intervals for 3 months, then monthly. Eligible pts were required to have a serum CEA > 5 ng/ml or > 20% CEA+ positive tumor block and no autoimmune history. An expansion cohort of 10 pts was enrolled to focus on IR. Pts had re-staging scans at 3 months, then bimonthly. Peripheral blood was collected for analysis of IR including the Effector/Regulatory T-cell ratio, ELISPOT assay, changes in the myeloid-derived suppressor cells (MDSC) and natural killer cells (NK). Results: 25 pts with progressive metastatic CEA-expressing carcinoma were enrolled; 22 had colorectal adenocarcinoma. Vaccine was well tolerated with no dose limiting toxicities. The most common adverse event was grade 1/2 injection site reaction. Overall, 7 patients had stabilization or declines in serum CEA after treatment. Of them, 5 pts (3 with colorectal cancer) had stable disease beyond 3 months and 1 is still on-going (14 +, 8, 8, 4.5 and 4 months). No anti-CEA antibodies were detected. Post vs. pre-vaccination: a) five out of 9 evaluable pts showed evidence by ELISPOT of CEA-specific T-cell IRs b) 8/16 pts had increased and 8/16 pts had decreased CD4 Effector/Treg ratio and c) 6/13 pts had increased and 2/13pts had decreased NK frequency. Conclusions: Saccharomyces cerevisiae-CEA demonstrated an acceptable safety profile. Although this is an advanced disease population of pts which is not ideal for immune-based therapy, CEA serum stabilizations and CEA-specific IRs were seen in some pts. Randomized studies are required to determine the clinical benefit of this vaccine in a more appropriate patient population for vaccine therapy.

CTLA4 and CD47 combinational therapy to extend survival in melanoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e21025-e21025
Author(s):  
Anthony L. Schwartz ◽  
Pulak Nath ◽  
Elizabeth Lessey-Morillon ◽  
Lisa Ridnour ◽  
Michael Allgaeuer ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Cell Activation ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Granzyme B ◽  
Suppressor Cells ◽  
Cell Infiltration

e21025 Background: Irradiation (IR) combined with chemotherapy is the post-surgical standard of care treatment for melanoma, but metastasis still results in high mortality rates. Immune checkpoint inhibitors such as cytotoxic T-lymphocyte antigen-4 (CTLA4) have proven effective for immunotherapy of melanoma. CTLA-4 is up-regulated post-T cell activation and blockade enhances tumor responses in immunocompetent rodents and humans. Trials suggest that combinations of immune checkpoint inhibitors are more efficacious than single agents, but tumors remain resistant. We are investigating CD47 blockade for the treatment of cancer. CD47 is frequently elevated in cancers and serves as an inhibitory receptor for thrombospondin-1 on immune cells in the tumor stroma. CD47 blockade on CD8 T or tumor cells significantly enhances immune-targeted tumor cell killing post-IR compared to IR alone. Here we explore the potential for antisense CD47 and anti-CTLA4 therapy alone or in combination with IR using a syngeneic mouse melanoma model. Methods: C57BL/6 mice were inoculated with 1x106B16F10 melanoma cells in the hind limb and treated with 10 Gy IR combined with CTLA4 blocking antibody, CD47 translational blocking morpholino, or the combination of CTLA4/CD47 therapies. Granzyme B along with CD4/CD8 T cell infiltration were examined in tumors. Histology was evaluated for CD3 and necrosis. Results: The combination of CD47/CTLA4 with IR significantly increased survival by 25% compared to IR/CTLA4 alone at 50 days. Granzyme B expression was significantly increased in IR mice with CTLA4/CD47 combination, which correlated with infiltration of CD8+ T cells and a concomitant decrease in Gr1+CD11b suppressor cells compared to controls. In non-IR tumors, histology revealed minimal necrosis, while all IR groups showed increased necrosis. Tumor IR in combination with CTLA4 or CD47 increased immune cell infiltration. However, the combination of IR with CTLA4/CD47 showed widespread necrosis. All groups treated with the CD47 exhibited focal hemorrhage, which was more extensive when combined with CTLA4. Conclusions: Results herein suggest IR combined CTLA4/CD47 checkpoint blockade provides a survival benefit by activating a beneficial adaptive immune response.

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