Browsing Over 346 Presentations
72P - Evaluation of the correlation between diverticulosis and the onset of diarrhea in patients with lung cancer treated with immune checkpoint inhibitors
- G. Negrini (Bergamo, Italy)
- G. Negrini (Bergamo, Italy)
- L. Ghilardi (Bergamo, Italy)
- L. Bonomi (BERGAMO, Italy)
- E. Arnoldi (BERGAMO, Italy)
- C. Tondini (BERGAMO, Italy)
- C. Sansi (BERGAMO, Italy)
- A. Bettini (BERGAMO, Italy)
Abstract
Background
Immune checkpoint inhibitors anti-PD-1 (Nivolumab and Pembrolizumab) represent a remarkable advance in non-small-cell lung cancer (NSCLC) treatment with impressive clinical activity and durable responses in some patients. However, immunotherapies generate new toxicity profiles called immune-related adverse events (irAEs) that require specific management. Gastrointestinal (GI) irAEs (diarrhea and colitis) are among the most common and if they are left unrecognised or untreated, they can become life threatening. Therefore, the identification of the risk factors for the development of diarrhea could be helpful for the prevention and management of GI irAEs. Among these, the presence of diverticulosis could affect the onset of diarrhea.
Methods
This retrospective analysis was conducted in 94 patients with metastatic NSCLC who received Nivolumab at the Papa Giovanni XXIII Hospital in Bergamo between 2015 and 2017. We evaluated the presence of diverticulosis before the start of immunotherapy, the degree and management of diarrhea during therapy and the correlation between the presence of diverticulosis and GI irAEs.
Results
All patients had previously been treated with chemotherapy. 90 patients received Nivolumab at a dose of 3mg/kg while 4 patients received Nivolumab flat dose of 240mg. The RR was 14% and the DCR was 45%. The median PFS has not yet been reached. 19 of 94 patients had a radiological diagnosis of diverticulosis before the start of treatment and 11 of 94 patients developed diarrhea during the therapy. While of the 75 patients without diverticulosis only 7% developed diarrhea, 32% of patients with diverticulosis developed diarrhea. The chi-square test was used for statistical analysis. GI irAEs were in most cases of grade 2 and were treated with steroid therapy without having to resort to other types of immunosuppressive therapy. No patient discontinued treatment due to adverse event.
Conclusion
In our population, the presence of diverticulosis increases the risk of gastrointestinal irAEs. However, these patients can be treated with immunotherapy but they represent a risk class for the onset of diarrhea. Further studies are needed to confirm our findings.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
General discussion / Q&A
111P - Pilot study on the feasibility, safety and immunogenicity of a personalized neoantigen-targeted immunotherapy (NeoPepVac) in combination with anti-PD-1 or anti-PD-L1 in advanced solid tumors
- S. Moerk (Herlev, Denmark)
- S. Moerk (Herlev, Denmark)
- M. Donia (Herlev, Denmark)
- J. Kringelum (Copenhagen K, Denmark)
- T. Bogenrieder (Copenhagen K, Denmark)
- B. Rønø (Copenhagen K, Denmark)
- A. Sorensen (Copenhagen K, Denmark)
- A. Draghi (Herlev, Denmark)
- K. Bol (Herlev, Denmark)
- N. Petersen (Copenhagen K, Denmark)
- M. Kadivar (Kgs. Lyngby, Denmark)
- S. Hernandez (Kgs. Lyngby, Denmark)
- S. Reker Hadrup (Copenhagen, Denmark)
- L. Andreasen (Kbh. S, Denmark)
- D. Christensen (Kbh. S, Denmark)
- P. Andersen (Herlev, Denmark)
- I. Svane (Herlev, Denmark)
Abstract
Background
The majority of neoantigens arise from unique mutations which are not shared between individual patients. Thus, neoantigen-directed immunotherapy is a fully personalized treatment. Novel technical advances in next-generation sequencing and artificial intelligence (AI) allow fast and systematic prediction of cancer neoantigens for each individual patient. In this study, the proprietary AI platform PIONEERTM is used for fast and accurate identification of tumor-derived neoantigens to be included in an immunotherapy (NeoPepVac), tailored to each individual patient. NeoPepVac immunotherapy, consisting of 5-15 predicted neoantigens as synthetic peptides, is formulated with a novel cationic liposomal adjuvant (CAF09b) to strengthen CD8+ T-cell immunity towards cancer. Immune checkpoint inhibitors, targeting PD-1 or PD-L1, are administered before, during and after neoantigen-targeted immunotherapy to augment the activity of induced immune responses.
Methods
The study is designed as an open phase I/IIa trial. Patients with either unresectable or metastatic melanoma, non-small cell lung cancer (NSCLC) or bladder (urothelial) cancer who meet the criteria for treatment with anti-PD-1 or anti-PD-L1 are included. The NeoPepVac immunotherapy is given every second week, for a total of 6 immunizations. Blood samples are collected before, during and after NeoPepVac treatment to monitor the induction of a neoantigen-specific immune response and immune-related changes.
Results
Four patients have been included and treated with personalized NeoPepVac immunotherapy. So far, only CTCAE Grade 1 mild flu-like symptoms have been observed as NeoPepVac-related AEs at the first dose level (500 mg total peptide). At least 50% of the neoantigens are generating a specific T-cell response as determined by IFN-γ ELISPOT analyses of patient PBMCs.
Conclusion
So far the vaccine is well tolerated and safe. Neoantigen prediction and immunotherapy manufacturing is feasible within 6 weeks of patient enrolment using the PIONEERTM platform. Preliminary analyses indicate induction of NeoPepVac-specific immune responses.
Clinical trial identification
EudraCT: 2018-002892-16.
Legal entity responsible for the study
Inge Marie Svane.
Funding
Innovations fonden.
Disclosure
J.V. Kringelum: Full / Part-time employment, PhD, Director, Genomic Immuno-Oncology: Evaxion. T. Bogenrieder: Full / Part-time employment, CMO at Evaxion: Evaxion. B. Rønø: Full / Part-time employment, PhD, Director, Cancer Vaccines: Evaxion. A.B. Sorensen: Full / Part-time employment, Project Manager, Personalized Immuno-oncology: Evaxion. N.V. Petersen: Full / Part-time employment: Evaxion. L.V. Andreasen: Leadership role: SSI. D. Christensen: Leadership role, Full / Part-time employment: SSI. P.L. Andersen: Leadership role, Full / Part-time employment: SSI. All other authors have declared no conflicts of interest.
Development and commercialisation of a first-in-class chimeric antigen receptor T-cell product for large cell lymphoma
- J. Rossi (Santa Monica, United States of America)
- J. Rossi (Santa Monica, United States of America)
145P - Immune-competent 3D InSightTM tumour models as novel platform to assess combinatorial biologics therapy
- F. Chiovaro (Schlieren, Switzerland)
- F. Chiovaro (Schlieren, Switzerland)
- N. Buschmann (Schlieren, Switzerland)
- S. Strebel (Schlieren, Switzerland)
- A. Wolf (Schlieren, Switzerland)
- I. Agarkova (Schlieren, Switzerland)
Abstract
Background
Immunotherapy has revolutionized cancer treatment, but clinical success is still limited to a subset of patients, underlining the need for novel therapeutic targets. Available ex vivo platforms for drug screening show limitations due to only partial recapitulation of tumor-intrinsic features and of the interactions of tumours with stromal/immune cells. Here, we review our 3D InSightTM tumour models, a complex platform allowing us to study the efficacy of immune-targeting agents on tumour infiltration and killing by peripheral blood mononuclear cells (PBMCs) using clinically relevant models of 3D tumour microtissues from patient-derived xenografts (PDX) with high translational potential.
Methods
Lung carcinoma GFP-A549 cells were cultured with dermal fibroblasts and PBMCs in Akura 96/384-well plates. To generate a pro-inflammatory tumour microenvironment, PBMCs were activated with cytokines, anti-CD3/CD28 or their combination. We assessed the effect of PD-1 inhibitors in combination with cytokines for potential synergistic anti-cancer effects. 3D InSight™ tumour Microtissue from Melanoma PDX were labeled with CellTracker to monitor for tumour cell viability once exposed to PBMCs. Killing activity and effector function of T cells were evaluated by measuring tumour microtissue size by automatic stage fluorescence microscopy and measuring release of IL-6, TNF, IFNγ and GM-CSF with a MAGPIXTM Luminex system over time. Immune tumour infiltration was quantified and the impact on survival was assessed histologically.
Results
Combination treatment with cytokines and anti-PD-1 led to higher release of IL-6/TNF/IFNγ/GM-CSF and increased tumour microtissue infiltration by CD8+ T cells, resulting in enhanced tumour killing.
Conclusion
Our 3D InSightTM tumour models can be successfully employed for optimal high throughput screening of biologics to unveil the efficacy and anti-tumour properties of immune-targeting therapeutic agents.
Legal entity responsible for the study
InSphero.
Funding
InSphero AG.
Disclosure
All authors have declared no conflicts of interest.
NK cells and ILCS and their immune checkpoints
- C. Jandus (Lausanne, Switzerland)
- C. Jandus (Lausanne, Switzerland)
Welcome & Introduction (ID 513)
Intra-tumoral RECIST: The complexity of non-enestic response
- L. Schwartz (New York, United States of America)
- L. Schwartz (New York, United States of America)
DOI session
129O - Resistance to immunotherapy is associated with high parenchymal PD1+CD8+/CD8+ T cells (PD1tR) driven by tumour CD155
- A. Lepletier de Oliveira (Brisbane, Australia)
- A. Lepletier de Oliveira (Brisbane, Australia)
- J. Madore (Brisbane, QLD, Australia)
- J. S. O’donnell (Brisbane, Australia)
- R. L. Johnston (Brisbane, QLD, Australia)
- M. Eastgate (Brisbane, QLD, Australia)
- D. Mallardo (Napoli, Italy)
- P. Ascierto (Napoli, Italy)
- D. Massi (Florence, Italy)
- B. Merelli (Bergamo, Italy)
- M. Mandala (Bergamo, Italy)
- J. S Wilmott (Sydney, NSW, Australia)
- T. Bald (Brisbane, QLD, Australia)
- J. Stagg (Montreal, QC, Canada)
- B. Routy (Montreal, QC, Canada)
- G. V. Long (Sydney, QLD, Australia)
- R. A. Scolyer (Sydney, Australia)
- N. Waddell (Brisbane, ACT, Australia)
- W. C. Dougall (Brisbane, QLD, Australia)
- M. W. L. Teng (Brisbane, QLD, Australia)
- M. Smyth (Brisbane, QLD, Australia)
Abstract
Background
We have previously shown that a possible complementary target to PD1-based immune-checkpoint blockade (ICB) is the adhesion molecule CD155, which promotes tumor growth and metastasis in mouse models. To date, it is unclear to what extent tumor CD155 expression impacts the immune infiltrate contexture or if expression of CD155 by human tumors affects sensitivity to ICB.
Methods
We assessed pretreatment tumor FFPE specimens from 146 metastatic melanomas patients treated with immune checkpoint blockade (ICB) and 41 patients that have received 1st line BRAF/MEK targeted therapy and no ICB. CD155 expression was defined by immunohistochemistry (IHC) H-score. The immune infiltrate was separately analysed in stroma and parenchymal (intratumor) regions using multiplex immunohistofluorescence (IHF) for CD8, PD1 and SOX10. Associations were made between IHC analyses, bulk tumor RNA-seq results, and immunotherapeutic response (RECIST, PFS, and disease specific OS). Key findings were functionally validated in a relevant mouse melanoma model.
Results
Melanoma patients with high levels of tumor CD155 (score 3+) frequently had progressive disease or shorter PFS through promotion of dysfunctional PD1+CD8+ T cells. Further, the intratumor ratio of PD1+CD8+ to total CD8+ T cells (PD1tR) is a strong predictor of ICB refractory patients. Importantly, outcome correlations appeared specific to ICB therapy and were not present in melanoma patients treated with BRAF/MEK targeted therapy. In humans, CD155 high tumors show reduced Interferon-gamma and cytotoxic gene signatures. In PD1 resistant mouse tumor models, deletion of CD155 prevented accumulation of intratumor PD1hiCD8+ T cells. Additionally, therapeutic blockade of the CD155 cognate receptors TIGIT and CD96 restored IFNγ production and improved anti-PD1 tumor control.
Conclusion
Our findings are the first to demonstrate that tumor CD155 underpins the accumulation of dysfunctional PD1hiCD8+ T cells in human tumors and propose pretreatment PD1tR as a potential biomarker of response to ICB.
Legal entity responsible for the study
The Council of the Queensland Institute of Medical Research.
Funding
Bristol-Myers Squibb.
Disclosure
P.A. Ascierto: Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (self): Roche-Genentech; Advisory / Consultancy, Research grant / Funding (self): Array; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy: Novartis; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Incyte; Advisory / Consultancy: Genmab; Advisory / Consultancy: Newlink Genetics; Advisory / Consultancy: Medimmune; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Syndax; Advisory / Consultancy: Sun Pharma; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Idera; Advisory / Consultancy: Ultimovacs; Advisory / Consultancy: Sandoz; Advisory / Consultancy: Immunocore. G. V. Long: Advisory / Consultancy: Aduro; Advisory / Consultancy: Amgen; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Merck MSD; Advisory / Consultancy: Novartis; Advisory / Consultancy: Roche. R. A. Scolyer: Advisory / Consultancy: Merck Sharp Dohme; Advisory / Consultancy: Novartis; Advisory / Consultancy: Myriad; Advisory / Consultancy: NeraCare. W. C. Dougall: Research grant / Funding (self): Bristol-Myers Squibb; Advisory / Consultancy: Omeros Corporation ; Advisory / Consultancy: Cascadia Drug Development Group. M. W. L. Teng: Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert testimony: MSD; Speaker Bureau / Expert testimony: Bristol-Myers Squibb. M. Smyth: Research grant / Funding (self): Bristol-Myers Squibb; Research grant / Funding (self): Aduro Biotech; Research grant / Funding (self): Tizona Pharmaceuticals. All other authors have declared no conflicts of interest.
36P - First CAR-T cell immunotherapy against HLA-G: Targeting a unique ICP and TAA
- M. Loustau (Paris, France)
- M. Loustau (Paris, France)
Abstract
Background
CAR-T cells therapies turn out to be a breakthrough, particularly for B-cell malignancies. However, its application in solid tumor remains a challenge. The main limitations are: few highly specific tumor associated antigen (TAA), low T cell penetration and an immune-suppressive tumor microenvironment (TME). Thus, our aim was to develop a new immunotherapeutic strategy against HLA-G, an immune-tolerogenic molecule involved in tumor immune escape, frequently upregulated on tumor cells. HLA-G is a CMH-Ib molecule and exerts its immuno-inhibitory activity through specific binding with two inhibitory receptors, ILT2 and ILT4, leading to the inhibition of all immune cell subsets and the induction of suppressive immune cells. HLA-G was recently identified as an ICP molecule, could be highly neo-expressed in cancer, i.e.: ccRCC (98%) and associated with malignant transformation. HLA-G is found on tumor cells and is rarely observed in healthy tissues defining it as a remarkable TAA. RNAseq analyses show that HLA-G is a far better tumor specific antigen than PD-L1. However, no immunotherapy against HLA-G-expressing tumors has been developed. Indeed, neither stimulatory functions nor cellular responses directed against allogeneic HLA-G have been reported.
Methods
Highly specific antibodies against HLA-G, generated by our team, strongly bind to multiple HLA-G isoforms and their scFv were used to develop 3rd generation chimeric antigen receptors (CARs).
Results
Anti-HLA-G CAR-T were specifically cytotoxic for HLA-G expressing target cells (K562-HLA-G1 and Jeg-3 cell lines), with resulting IFNg secretion and activation phenotype and also inducing a long-term T effector memory phenotype. Finally, in vivo assays demonstrated that anti-HLA-G CAR-T cells had strong anti-tumor activity controlling tumor progression up-to 50 days of experiment.
Conclusion
We report here for the first time CAR-T cells specifically targeting HLA-G expected to disrupt the tumor micro-environment related to HLA-G and solid tumors.
Legal entity responsible for the study
Invectys (Paris, France).
Funding
Invectys (Paris, France).
Disclosure
The author has declared no conflicts of interest.
101P - Results of the NLG2105 phase I trial using the IDO pathway inhibitor indoximod, in combination with radiation and chemotherapy, for children with newly diagnosed DIPG
- T. Johnson (Augusta, United States of America)
- T. Johnson (Augusta, United States of America)
- D. Aguilera (Atlanta, United States of America)
- A. Al-Basheer (Augusta, United States of America)
- Z. Berrong (Augusta, United States of America)
- R. Castellino (Atlanta, United States of America)
- B. Eaton (Atlanta, United States of America)
- N. Esiashvili (Atlanta, United States of America)
- N. Foreman (Aurora, United States of America)
- I. Heger (Dallas, AL, United States of America)
- E. Kennedy (Ames, AL, United States of America)
- N. Vahanian (Ames, AL, United States of America)
- W. Martin (Augusta, United States of America)
- R. Pacholczyk (Augusta, United States of America)
- E. Ring (Augusta, United States of America)
- R. Sadek (Augusta, United States of America)
- A. Smith (Orlando, AL, United States of America)
- M. Shimoda (Augusta, United States of America)
- T. Macdonald (Atlanta, United States of America)
- D. Munn (Augusta, United States of America)
Abstract
Background
We conducted a phase Ib dose-confirmation study of indoximod with radiation, followed by indoximod with cyclic temozolomide therapy, to evaluate safety and overall survival (OS) in children with newly diagnosed DIPG (diffuse intrinsic pontine glioma). Indoximod is a small-molecule inhibitor of the IDO pathway that reverses immune suppression imposed by tumor microenvironments. DIPG is a uniformly fatal orphan disease with no curative treatment options.
Methods
Children age 3 to 21 years, with newly diagnosed DIPG were eligible for treatment with oral indoximod (38.4 mg/kg/day divided BID, throughout) combined with fractionated conformal radiation therapy (54 Gy in 30 fractions), followed by cyclic oral chemo-immunotherapy using indoximod combined with temozolomide (200 mg/m2/day, days 1-5 of each 28-day cycle). The indoximod dose was the previously determined recommended phase-II dose (RP2D), and the study design called for phase I monitoring to confirm safety of this dose in DIPG patients.
Results
Thirteen children (median age 9 years, range 5 to 20 years) with newly diagnosed DIPG were treated using this indoximod-based radio-chemo-immunotherapy regimen. The 12-month OS was 62% (8/13) and estimated median OS was 14.5 months (follow-up range 4.8 to 22 months) with 4 patients remaining in follow-up. This compares favorably to the expected 12-month OS of approximately 45% and median OS of approximately 10.8 months from published historical controls (Kilburn, et al; 2017). Two patients experienced near-complete responses until showing relapse at 7.6 months and 13.3 months of study therapy. Patients were followed with quantitative volumetric analyses of MRIs and serial measurements of peripheral blood inflammatory monocytes, T cell activation, and pro-inflammatory cytokines. The most common adverse events attributed to indoximod were thrombocytopenia, diarrhea, nausea, vomiting, and fatigue.
Conclusion
Adding indoximod-based immunotherapy to conventional radiation and chemotherapy for up-front therapy of children with DIPG appears to be well tolerated with improved outcomes.
Clinical trial identification
NLG2105, NCT02502708.
Legal entity responsible for the study
NewLink Genetics Corporation.
Funding
NewLink Genetics Corporation, Alex\'s Lemonade Stand Foundation, Cannonball Kids cancer Foundation, Beloco Foundation, Eli’s Block Party Foundation, Hyundai Hope on Wheels Foundation, Northern Nevada Children’s Cancer Research Foundation, CAM Fund, Press On Foundation.
Disclosure
T.S. Johnson: Research grant / Funding (institution): NewLink Genetics Corporation. E.P. Kennedy: Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: NewLink Genetics Corporation. N. Vahanian: Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: NewLink Genetics Corporation. D.H. Munn: Advisory / Consultancy, Shareholder / Stockholder / Stock options, Licensing / Royalties: NewLink Genetics Corporation. All other authors have declared no conflicts of interest.