Browsing Over 191 Presentations
Experience of immune-related adverse events associated with anti-CTLA-4 and anti-PD1 checkpoint inhibitors in a single center
- Bernardo L. Rapoport
- Bernardo L. Rapoport
- Teresa Smit
- Ronwyn I. Van Eeden
Abstract
Background
Ipilimumab (IPI), nivolumab (NIVO) and pembrolizumab (PEMBRO) can induce immune-related adverse events (IrAEs). We describe the IrAE’s associated with 64 patients (pts). There were 20 pts treated with IPI and 25 pts treated with NIVO, 18 pts received PEMBRO alone or in combination with either epacadostat or Talimogene Laherparepvec (T-VEC), and 1 pt was treated with combination of IPI and NIVO.
Methods
Retrospective data from 64 pts were used treated either in an expanded access programme, clinical trial setting or post-registration protocol.
Results
A total of 64 pts (33 males, 31 females) were analyzed. Three pts with metastatic malignant melanoma (MMM), 18 with non-small cell lung cancer (NSCLC), 2 with renal cell carcinoma and 2 with Hodgkin’s disease were treated with NIVO and 20 with MMM received IPI. The PEMBRO group consisted of 3 breast cancer, 2 ovarian, 1 stomach and 12 MMM pts. One NSCLC pt received combination of IPI and NIVO (1 cycle). In total 167 cycles of NIVO (median = 4, range 1-16), 123 cycles of PEMBRO (median = 4, range 1-26), and 64 cycles of IPI (median = 4 cycles, range 1-4) were administered. Seven IrAEs are described in 15 IPI treated pts. These included endocrinopathy in 3 pts, colitis in 3 pts (1 required infliximab) and hepatitis in 1 pt. Among the pts treated with NIVO, 7 IrAEs were documented. These included pneumonitis in 2 pts, skin rash in 3 pts, mild diarrhea in 1 pt and mild uveitis in 1 pt. One pt developed autoimmune thrombocytopenia, nephritis, and PRES (posterior reversible encephalopathy syndrome). Three chest infections were documented including pulmonary tuberculosis in a NSCLC pt. Among the pts treated with PEMBRO, 10 IrAE were documented. These included 4 dermatological, 1 Bell’s palsy, 3 mild diarrhea and 2 hypothyroidism. The pt receiving combination IPI and NIVO had grade 4 skin toxicity. No IrAE related deaths were document.
Conclusions
A plethora of irAEs are described with anti-PD1 and anti-CTLA4 antibodies. Colitis was more common with IPI while pneumonitis more common with NIVO. Prompt diagnosis of IrAE’s will result in decreased morbidity and mortality.
Legal entity responsible for the study
Prof Bernardo L. Rapoport
Funding
None
Disclosure
B.L. Rapoport: MSD (advisory board, consultancy, speaker engagements, and contract research); BMS South Africa (advisory board, consultancy, speaker engagements, research grant and contract research); Amgen South Africa (advisory board, consultancy, speaker engagements, and contract research). All other authors have declared no conflicts of interest.
Modulation of the tumor microenvironment by the TLR9 agonist EnanDIM and combination with checkpoint inhibition for cancer immunotherapy
- Kerstin Kapp
- Kerstin Kapp
- Barbara Volz
- Detlef Oswald
- Burghardt Wittig
- Manuel Schmidt
Abstract
Background
The EnanDIM® family consists of linear single-stranded DNA molecules containing non-methylated CG-motifs for TLR9 activation and L-deoxyribonucleotides at their 3’-ends to prevent degradation. They initiate a broad activation of the innate and adaptive immune system. The conversion of non-immunogenic (“cold”) tumors into immunogenic (“hot”) tumors, characterized by their T cell infiltration, is a pre-requisite for a response to checkpoint inhibitors. This may be achieved by EnanDIM® due to induced IP-10/CXCL10 secretion. Furthermore, the mode-of-action of EnanDIM® starts upstream of the initiation points of checkpoint inhibitors (CPI). Therefore EnanDIM® likely provides the relevant immune activation required for effectiveness of CPI and thus resulting in an enhanced anti-tumor effect in combination approaches.
Methods
The colon carcinoma model CT26 was used for evaluation of the influence of EnanDIM® on the tumor microenvironment (TME) and to investigate the anti-tumor effect of EnanDIM® in combination with anti-PD-1. In addition, the impact of EnanDIM® on T cell responses was analyzed employing an in vitro assay with human peripheral blood mononuclear cells (PBMC) stimulated with CEF-peptides recognized by recall-antigen-specific CD8+ T cells (
Results
An increased infiltration of T cells, especially CD8+ T cells, into the tumor was associated with an anti-tumor response after intratumoral injection of EnanDIM® in the CT26 model. The moderate anti-tumor effect of aPD-1 was substantially augmented by a combination with EnanDIM®. After stimulation with CEF-peptides, human PBMC were treated with either EnanDIM® or aPD-1. Resulting IFN-gamma secretion was higher for EnanDIM® than for aPD-1 and was further enhanced by the combined treatment.
Conclusions
TLR9 agonist EnanDIM® activated CD8+ cytotoxic T cells and initiated their infiltration into the tumor complementing the mode-of-action of CPI. Indeed EnanDIM® enhanced the limited anti-tumor effect of aPD-1 in a murine colon carcinoma model in vivo. These data show the promising potential of EnanDIM® for the combination with CPI in clinical trials.
Legal entity responsible for the study
Mologen AG
Funding
Mologen AG
Disclosure
K. Kapp, B. Volz, D. Oswald, M. Schmidt: Employee at Mologen AG. B. Wittig: Stock ownership, consults Mologen
Abundance of Treg cells in oral cancer patients and effects of their inhibition on growth of cancer cells
- Sadhna Aggarwal
- Sadhna Aggarwal
- Satya N Das
- Suresh C. Sharma
Abstract
Background
Oral squamous cell carcinoma (OSCC) is one of the major cancers affecting Asian countries. The main causative factor has been the tobacco habit. It has been reported that immune dysfunction in these patients is one of the major factors for tumor growth and dissemination that affects disease-free survival of the patients.
Methods
We assessed the phenotypic and functional characteristics of Regulatory T (Treg) CD4+CD25+FoxP3+subsets in patients (n = 53) with OSCC and healthy individuals (n = 30) by multicoloured flow cytometry. Subsequently we investigated the effects their inhibition via TDG on growth of OSCC cell lines in vitro.
Results
An increased (p < 0.05) prevalence of Treg phenotypes (CD4+CD25+, CD4+FoxP3+, CD8+FoxP3+, CD4+CD25+FoxP3+) was observed in the peripheral circulation of OSCC patients that positively correlated with clinicopathological features. The increased frequency of CD4+CD8+CD25+FoxP3+, a unique T cell subset, CTLA4+, GITR+, NrP1+ and granzyme B + (GzmB) Tregs also showed a significantly higher prevalence in OSCC patients. Functionally CD4+FoxP3+ Tregs showed skewed expression of IL2, IL10 and IL35 in patients as compared with the normal controls. Higher expression of TGFβ in tumor tissues suggests their dominant role in the up regulation of differentiation of Tregs from naive T cells in the tumor bearing host. Further, enhanced expression of CCR5 and CCR7 on Tregs with up regulation of their ligands (CCL5, CCL19 and CCL21) in tumor cells indicates efficient recruitment and trafficking of Tregs to the tumor site. Treatment with βGBP showed growth promoting effects on Tregs and oral cancer cells. However, the treatment with its inhibitor TDG resulted in inhibition of Treg subsets and also decreased the frequency of IL10+ and IL35+ Tregs indicating its immunomodulatory effects.
Conclusions
Hence, it seems reasonable to assume that modulation of functional dynamics of selective Treg subsets may be useful in enhancing anti-tumor immunity and developing immunotherapeutic strategies for patients with oral squamous cell carcinoma.
Legal entity responsible for the study
Sadhna Aggarwal
Funding
None
Disclosure
All authors have declared no conflicts of interest.
Multiparameter investigations and the future of protein analysis
- Periklis Foukas
- Periklis Foukas
Cancer neoantigens and clonal dominance
- Marco Gerlinger
- Marco Gerlinger
Is there a place for checkpoint inhibition?
- Pierre-Yves Dietrich
- Pierre-Yves Dietrich
Optimizing the tolerability of intravenous oncolytic viral immunotherapy administration: A sub-analysis of tolerability and cytokine data from the EVOLVE study of enadenotucirev (EnAd), an oncolytic adenovirus
- Hilary McElwaine-Johnn
- Hilary McElwaine-Johnn
- Gillian Pover
- Simon Alvis
- Richard Brown
- Kerry Fisher
- Charles Morris
- Brian Champion
- John Beadle
Abstract
Background
EnAd is a tumor-selective oncolytic adenovirus with highly selective replication and cell killing in a broad range of carcinoma cell lines and little replication in normal and non-carcinoma cells. Following intravenous (IV) dosing in clinical studies, uptake and replication of EnAd, associated with CD8+ cell infiltration, has been shown in various carcinomas.
Methods
EVOLVE was a Phase 1 study to primarily explore the safety and efficacy of EnAd following IV administration of doses from 1e10 to 1e13 viral particles. Treatment cycles comprised IV infusions on Days (D) 1, 3 and 5, repeated every 3 weeks. Initial safety data have been reported elsewhere (ASCO 2014, abstr 3103). Here we present an analysis of the incidence and timing of adverse events (AEs) alongside the cytokine response data.
Results
During dose escalation, DLTs of acute lung injury, dyspnoea and hypoxia were reported at the highest dose tested, occurring on Cycle 1 Day 1 (C1D1). At doses up to the maximum tolerated dose (MTD), a higher incidence of AEs was reported following dosing on C1D1 compared with D3 & D5. Following D1 administration in Cycle 2, the frequency of AEs was lower than that reported on C1D1. Dose-dependent transient increases in MCP-1 and IL-6 were observed in all patients following C1D1 dose, with lower average increases following D3 & D5 administration, or on D1 of subsequent cycles. This pattern of cytokine release tends to mirror that of reported AEs, and appears independent of the anti-EnAd antibody response.
Conclusions
Tolerability of EnAd is primarily determined by C1D1, correlating with the cytokine response across the patient cohort. This supports the hypothesis that tolerability of the C1D1 dose of EnAd is limited by the activation of innate immune cells (for example, Kuppfer cells in the liver) with associated cytokine release. The MTD of EnAd has been determined primarily based on AEs occurring on C1D1, however higher subsequent doses may be tolerable. Manipulation of dosing regimens may allow administration of higher doses of EnAd on D3 & D5, and/or more doses per cycle, to increase EnAd delivery to tumor and optimize its immunotherapeutic potential.
Clinical trial identification
EUDRACT: 2012-001067-79
Legal entity responsible for the study
PsiOxus Therapeutics Ltd.
Funding
PsiOxus Therapeutics Ltd.
Disclosure
H. McElwaine-Johnn, S. Alvis, R. Brown, K. Fisher, C. Morris, B. Champion: Paid employee and stockholder of PsiOxus Therapeutics Ltd. G. Pover: Paid consultant of PsiOxus Therapeutics Ltd. J. Beadle: Paid employee, director and stockholder of PsiOxus Therapeutics Ltd.
miR-4317, a novel tumor suppressor miRNA, alleviates immune-suppressive microenvironment induced by breast cancer
- Rana A. Youness
- Rana A. Youness
- Reem A. Assal
- Hafez M. Hafez
- Amira Abdelmotaal
- Mohamed Z. Gad
Abstract
Background
Immunotherapy is revolutionizing the field of oncology and specifically Breast Cancer (BC). Immune exclusion phenomenon that is orchestrated by immune-suppressive cytokines acts as a formidable barrier towards efficient harnessing of tumor cells. Interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) play a pivotal role in shaping the tumor microenvironment and the magnitude of immune resistance. Finding molecular weapons to efficiently harness BC progression, enhance immune cells cytotoxicity and most importantly alleviates the tumor-induced immune suppressive microenvironment was our main goal. microRNA-4317 is a novel miRNA that was reported to have an alerted expression pattern in several malignancies. Thus our aim was to unravel the mechanistic role of miR-4317 in BC patients and to investigate its impact on the tumor microenvironment.
Methods
Breast tissues were collected from 40 BC patients. MDA-MB-231 and MCF7 cells were cultured and transfected with miR-4317 oligonucleotides. Total RNA was extracted and quantified by qRT-PCR. Cellular proliferation and anchorage independent growth were measured using BrdU and colony forming assays respectively. Cell culture supernatants were screened for IFN-γ and TNF-α using Human IFN-γ and TNF-α Elisa kits, respectively.
Results
miR-4317 was found to be specifically down-regulated in BC tissues compared to its normal counterparts. TNBC patients showed the lowest levels of miR-4317. In parallel, the aggressive TNBC cells, MDA-MB-231 showed more reduced expression levels of miR-4317 compared to hormone receptor positive BC cells, MCF7. Mechanistically, ectopic expression of miR-4317 resulted in a significant decrease in cellular proliferation rate and anchorage independent ability of BC cell lines. Additionally, a potent repression of TNF-α release in cellular supernatant was observed together with an increase in IFN-γ levels thus restoring the immune-stimulating conditions at the tumor microenvironment.
Conclusions
miR-4317 acts as a novel tumor suppressor miRNA. Moreover, it has a potent impact in alleviating the tumor induced immune-suppressive microenviroment. Thus suggesting miR-4317 as a novel therapeutic agent in BC.
Legal entity responsible for the study
German University in Cairo
Funding
None
Disclosure
All authors have declared no conflicts of interest.
CAR T cells for haematological malignancies and solid tumours
- Caroline Arber Barth
- Caroline Arber Barth
Immunoscore and immunoprofiling in cancer
- Zlatko Trajanoski
- Zlatko Trajanoski
Combination immunotherapy: Effects of simultaneous targeting of different mechanisms
- David Feltquate
- David Feltquate
Selective internal radiation therapy (SIRT) promotes the recruitment of tumor-infiltrating lymphocytes and enhances cytotoxic activity in hepatocellular carcinoma
- Ligia Craciun
- Ligia Craciun
- Roland De Wind
- Pieter Demetter
- Valerio Lucidi
- Sebastien Michiels
- Soizic Garaud
- Céline Naveaux
- Maria Gomez Galdon
- Alain Hendlisz
- Karen Willard Gallo
- Patrick Flamen
- Denis Larsimont
- Vincent Donckier
Abstract
Background
Intra-arterial therapies, including transarterial chemoembolization (TACE) and selective internal radiation therapy with 90Yttrium (SIRT), are effective locoregional treatments for hepatocellular carcinoma (HCC). High levels of tumor-infiltrating lymphocytes (TILs) are associated with a better prognosis in HCC. We hypothesized that TACE and SIRT may modify immunogenic tumor microenvironment. To analyze this question, we evaluated TILs in patients who underwent partial hepatectomy for HCC after preoperative TACE or SIRT and in patients operated without preoperative treatment (SURG).
Methods
Epidemiological, clinical and pathological data were analyzed in SIRT (n = 12), TACE (n = 16) and SURG (n = 32) groups. Sections for digital image analysis (DIA) were prepared from paraffin blocks. Immunohistochemistry stains were performed for CD3, CD4, CD8, CD20 and Granzyme B. The slides were scanned and analyzed with DIA Visiopharm software. After exclusion of the necrotic zones, TILs were quantified as percentages of positive cells/analyzed area.
Results
Baseline patient and tumor characteristics were similar in the 3 groups. Median times between SIRT or TACE and partial hepatectomy were not significantly different (16 versus 11 weeks). In resected HCC, preoperative SIRT significantly increased CD3+ TILs, including both CD4+ and CD8+ subpopulations, as compared to TACE and SURG groups. Preoperative TACE did not significantly affect TILs, neither for CD3+ nor for CD4+ or CD8+ subpopulations, as compared to the SURG group. CD20+ B lymphocyte infiltrates were similar in the 3 groups. Significantly increased expression of Granzyme B was demonstrated in SIRT patients while no modification of Granzyme B levels was observed between TACE and SURG patients.
Conclusions
In contrast with TACE, SIRT increases TILs levels and intratumor cytotoxic activity in HCC. These results suggest that local attraction/activation of effector T cells may contribute to the anti-tumor effect of SIRT, supporting the clinical development of therapeutic approaches combining SIRT and immunotherapy.
Legal entity responsible for the study
Vincent Donckier
Funding
None
Disclosure
All authors have declared no conflicts of interest.