Browsing Over 268 Presentations
83P - Optimising TNFRSF agonism and checkpoint blockade with a novel CD137/PD-L1 bispecific antibody (ID 444)
- M. A. Lakins (Cambridge, United Kingdom)
- M. A. Lakins (Cambridge, United Kingdom)
- J. Munoz-Olaya (Cambridge, United Kingdom)
- D. Jones (Cambridge, United Kingdom)
- R. Giambalvo (Cambridge, United Kingdom)
- C. Hall (Cambridge, United Kingdom)
- A. Knudsen (Cambridge, United Kingdom)
- N. Masque Soler (Cambridge, United Kingdom)
- S. Pechouckova (Cambridge, United Kingdom)
- E. Goodman (Cambridge, United Kingdom)
- C. Gradinaru (Cambridge, United Kingdom)
- A. Koers (Cambridge, United Kingdom)
- S. Marshall (Cambridge, United Kingdom)
- M. Wydro (Cambridge, United Kingdom)
- F. Wollerton (Cambridge, United Kingdom)
- S. Batey (Cambridge, United Kingdom)
- D. Gliddon (Cambridge, United Kingdom)
- M. Davies (Cambridge, United Kingdom)
- M. Morrow (Cambridge, United Kingdom)
- M. Tuna (Cambridge, United Kingdom)
- N. Brewis (Cambridge, United Kingdom)
Abstract
Background
PD-1/L1 axis blockade shows durable responses and extended overall survival across cancer types in a subset of patients. Tumour Necrosis Factor Receptor (TNFR) superfamily activation is also being tested clinically to improve patient responses. Current interventions using therapeutic CD137 agonists to activate T cells are limited by adverse safety effects and poor efficacy as monotherapies. The generation of a bispecific agonist of CD137 following PD-L1 crosslinking allows a greater therapeutic window with improved safety and efficacy.
Methods
An anti-CD137/PD-L1 mAb2 was generated by introducing a CD137-binding specificity into the Fc-region of a human IgG1 targeting PD-L1 mAb. FcgR binding was decreased by introducing a LALA mutation. Binding characterisation was assessed and in vitro activity measured in a mouse primary OT-1 CD8+ T cell assay. The anti-tumour activity and PK/PD of anti-CD137/PD-L1 mAb2 was tested in mouse tumour models.
Results
An anti-CD137/PD-L1 mAb2 was developed, which binds to mouse PD-L1 enabling CD137 agonism (in vitro EC50: 3 pM in primary antigen-specific OT-1 assay). The mAb2 significantly reduced tumour growth in 3 syngeneic mouse tumour models (MC38, CT26 and B16-F10) with dose-dependent inhibition seen in CT26, resulting in a significant survival benefit at concentrations of 0.3 mg/kg or above. This growth inhibition was coincident with increases in tumour and peripheral activated CD8 T cells. Liver pharmacology was minimal as defined by histopathology.
Conclusions
We report intra-tumoural and peripheral PD changes leading to an increase in the proliferative CD8+ T cell response following dosing with an anti-CD137/PD-L1 bispecific mAb2. These changes were dose dependent and coincident with tumour growth inhibition. In in vitro T cell activation assays the bispecific was superior to control antibodies and relevant combinations. Minimal liver pharmacology and no toxicity was observed with the anti-CD137/PD-L1 mAb2 unlike with other monoclonal antibodies targeting CD137. This warrants the development of a first-in-class anti-human CD137/PD-L1 bispecific antibody with a novel mode of action and improved therapeutic index for the treatment of human cancer.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
Adoptive cell therapy in melanoma (ID 43)
- J. B. Haanen (Amsterdam, Netherlands)
- J. B. Haanen (Amsterdam, Netherlands)
DOI session (ID 518)
Directing the immune system with neoantigen therapeutics (ID 106)
- R. B. Gaynor (Cambridge, Indianapolis, United States of America)
- R. B. Gaynor (Cambridge, Indianapolis, United States of America)
4P - Prospective study of circulating tumor cells in long survivors of immunotherapy (ID 334)
- M. A. Brenes Fernández (Madrid, Spain)
- M. A. Brenes Fernández (Madrid, Spain)
- A. Garcia Grande (Madrid, Spain)
- F. Franco (Madrid, Spain)
- M. Coronado (Madrid, Spain)
- V. Calvo (Madrid, Spain)
- L. Gutierrez Sanz (Madrid, Spain)
- J. C. Sanchez (Madrid, Spain)
- M. Torrente Regidor (Madrid, Spain)
- B. Núñez (Madrid, Spain)
- R. Gómez Bravo (Madrid, Spain)
- M. Provencio Pulla (Majadahonda, Madrid, Spain)
Abstract
Background
Up to date, there isn’t current method or parameter that allows identifying long survivors in treatment with immunotherapy (IT) in a simple and accessible way. We made a prospective study of the usefulness of quantifying circulating tumor cells (CTCs) and CTCs/PDL1+ in patients treated with immunotherapy.
Methods
Patients, diagnosed with non-small cell lung cancer and in second-line treatment with IT were analyzed prospectively. CTCs from peripheral blood samples were isolated by double density gradient and immunomagnetic separation with AutoMACS equipment (M.Biotec). Quantification of CTCs was performed by Cytometry and Confocal Microscopy. The combination of both methodologies allows greater sensitivity and specificity. Samples were acquired in a MACSQuant cytometer (M.Biotec) and TCS SP5 Confocal Microscope (Leica).Data analysis was performed using MACSQuantify and LASF Lite. Determination of CTCs was made at the beginning of the treatment and every 3 months and up to 12 months during IT, together with radiological evaluation in each extraction. We selected those patients who had no progression of the disease for at least 12 months.
Results
Determination of CTCs alone did not allow us to obtain any pattern of recurrence or response. However, we were able to identify 7 patients in the group of long survivors (> 12 months of treatment with IT) using the marker PDL1. The study of their CTCs showed that none of them had circulating CTCs+/PD-L1+. Two of these patients were PDL1+ in tissue sample but negative CTC/PDL1 in blood. We also observed the presence of non-tumor WBC (white blood cells)/PDL1+, but their meaning is not clear in patients with relapse. To emphasize, another patient PDL1 + in tissue, CTC/PDL1+ in serum and low number of WBC, showed positive imaging (PET) of the progression of the disease and its CTC number increased in later determinations.
Conclusions
The absence of circulating CTCs/PDL1 + can predict a sustained response to long-term IT. Isolated CTCs without quantifying their associated expression of PDL1 are not associated with a particular pattern nor appear to be useful in identifying long survivors. WBCs that express PDL1 were associated with the appearance of relapse. Larger studies are needed to validate our results.
Legal entity responsible for the study
Hospital Universitario Puerta de Hierro Majadahonda.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
40P - Interest and potential of genetically engineered cord blood derived T cells for cancer immunotherapy (ID 364)
- C. Marton (Besançon, France)
- C. Marton (Besançon, France)
- P. Mercier-Letondal (Besançon, France)
- M. Deschamps (Besançon, France)
- C. Ferrand (Besançon, France)
- O. Adotevi (Besançon, CEDEX, France)
- C. Borg (Besançon, CEDEX, France)
- J. Galaine (Besançon, France)
- Y. Godet (Besançon, France)
Abstract
Background
The use of engineered T cells has proven to be successful in the field of cancer therapy. In vivo persistence of these genetically redirected T cells, which depends on their differentiation profile, plays a central role in the achievement of treatment efficacy. Indeed, less differentiated T cells proliferate and persist longer in vivo compared to their more differentiated counterparts, while having functional antitumor capacities. In this view, cord blood derived T cells display a more naïve phenotype compared to peripheral blood derived T cells. Hence, cord blood could be used as a source of T cells in order to generate gene-modified cancer-targeting cells able to persist in vivo, with the ability to ensure immunosurveillance in treated patients.
Methods
Cord blood derived T cells were isolated, activated and cultured with IL-2 or IL-7 and IL-15, before a retroviral transduction with a vector encoding a TCR targeting HPV16-E7/HLA-DR4. Transgenic T cell functional capacities were then evaluated by flow cytometry. The differentiation profile of cord blood derived T cells, genetically redirected or not and cultured in different conditions, were also analyzed.
Results
The IL-7 and IL-15 culture condition resulted in the generation of gene-modified T cells maintaining a higher transgenic TCR expression over time compared with the IL-2 culture condition. Functional assays revealed that genetically redirected T cells cultured in both conditions were reactive against HLA-DR4+ BLCL pulsed with an E7-derived peptide. Both T cell products lead to comparable interferon-γ, tumor necrosis factor-α and interleukine-2 secretion. These results are consistent with the fact that no outstanding difference was detected between both culture conditions regarding transduced and untransduced T cell differentiation profile.
Conclusions
In conclusion, we were able to generate cord blood derived transgenic T cells which were specific for an HPV16-E7 peptide, with a higher TCR expression over time when cultured with IL-7 and IL-15. Our study supports that cord blood units could be used as a source of T cells to develop cost-reducing and easy to access adoptive cancer immunotherapy.
Legal entity responsible for the study
UMR1098: INSERM, EFS BFC, Univ. Bourgogne Franche-Comté.
Funding
This work was supported by the Ligue Nationale Contre le Cancer, and by the MiMedi project funded by BPI France (grant No. DOS0060162/00) and the European Union through the European Regional Development Fund of the Region Bourgogne-Franche-Comte (grant No. FC0013440). C.M. has benefited from a fellowship from Nancy Regional University Hospital.
Disclosure
All authors have declared no conflicts of interest.
78P - Novel CTLA4 antibodies demonstrate potent anti-tumor activity in humanized CTLA4 mouse model (ID 465)
- C. Guo (Beijing, China)
- C. Guo (Beijing, China)
- Y. Yang (Beijing, China)
- Y. Guo (Beijing北京, China)
- Y. Shen (Beijing北京, China)
- J. Ni (Beijing, China)
Abstract
Background
CTLA4 (cytotoxic T-lymphocyte-associated protein 4) is homologous to the co-stimulatory protein CD28, and both receptor binds to CD80 and CD86. Cancer cells can be recognized and destructed by the host’s immune system. In this setting, CTLA4 functions as a brake to dampen anti-tumor T cell responses, which promote cancer progression. Antibodies targeting CTLA4 was expected to subvert T cell inhibition. Moreover, regulatory T cells residing in the tumor microenvironment can be killed by anti-CTLA4 antibody since these cells have higher expression level of CTLA4 comparing with the activated T cells. Yervoy, an anti-CTLA4 antibody, was the first FDA-approved antibody targeting the immune checkpoint family, and it protects a fraction of cancer patients when either used alone or in combination with other drugs. We asked whether the efficacy of anti-CTLA4 antibodies could be evaluated in humanized mouse models. And if so, whether we can use in vivo assay to guide the development of potent antibodies targeting CTLA4.
Methods
Here, we generated humanized CTLA4 knock-in mouse (B-hCTLA4) with a chimeric PD-1 receptor and this mouse were validated by Yervoy. Then, we utilized humanized B-hCTLA mice and implanted syngeneic tumors subcutaneously, followed by treating mice with purified testing CTLA4 antibodies and Yervoy. Via this approach, we are able to discern several clones that have better efficacy than Yervoy. These clones were further selected for humanization. The cohort of recombinant humanized CTLA4 antibodies were screened in B-hCTLA4 mice.
Results
We successfully generated B-hCTLA4 mouse for anti-human CTLA4 antibody in vivo efficacy evaluation. A cohort of CTLA4 specific antibodies were successfully generated and purified. The clones with better efficacy than Yervoy were screened using Biocytogen’s humanized mouse platform. These clones were humanized and screened by using B-hCTLA4 mice. Both the Fv and Fc portion of the lead antibody were optimized using the B-hCTLA4 mice, leading to the humanized form of the antibodies.
Conclusions
Using the platform established at Biocytogen, we successfully discovered two antibodies whose efficacy is equivalent or exceed that of Yervoy. The clinical evaluation of these new entities are wanted.
Legal entity responsible for the study
Yi Yang.
Funding
Beijing Biocytogen Co., Ltd.
Disclosure
All authors have declared no conflicts of interest.
The role of immunotherapy in mesothelioma (ID 38)
- J. G. Aerts (Rotterdam, Noord Brabant, Netherlands)
- J. G. Aerts (Rotterdam, Noord Brabant, Netherlands)
110TiP - A phase I dose escalation trial evaluating the impact of an in situ immunization strategy with intra-tumoral injections of Pexa-Vec in combination with ipilimumab in advanced solid tumors with injectable lesions (ID 425)
- A. Marabelle (Villejuif, France)
- A. Marabelle (Villejuif, France)
- L. Eberst (Lyon, Cedex 08, France)
- C. Terret (Lyon, CEDEX, France)
- F. Pilleul (Lyon, France)
- C. Mastier (Suresnes, France)
- A. Bouhamama (Lyon, France)
- L. Gilles-Afchain (Lyon, France)
- S. Laurent (Lyon, France)
- I. Delzano (Lyon, France)
- C. Reynaud (Lyon, France)
- C. Caux (Lyon, France)
- C. Caux (Lyon, France)
- G. Garin (Lyon, France)
- A. Bidaux (Lyon, France)
- D. Perol (Lyon, CEDEX, France)
- N. Stojkowitz (Illkirch-Graffenstaden, France)
- M. Homerin (Paris, France)
- H. Leenders (Paris, France)
- P. Cassier (Lyon, France)
Abstract
Background
In situ immunization is a strategy where immunomodulatory products are injected into one tumor site in order to use the tumor as its own vaccine and to trigger a systemic anti-tumor immune response. The Pexa-Vec (JX-594, Transgene) is an oncolytic virus genetically modified to secrete GM-CSF. We formulate the hypothesis that IT treatment with this oncolytic virus could synergize with anti-CTLA4 therapy via oncolytic virus-induced tumor cell death & tumor-antigen release, GM-CSF-induced recruitment/maturation/activation of antigen presenting cells, and anti-CTLA4-induced Treg blockade/depletion and reversion of T effectors inhibition.
Trial design
ISI-JX is a multicentric, Phase I dose escalation trial followed by an extension part aiming to evaluate the safety, feasibility, and anti-tumor effects of an in situ immunization strategy with IT injections of ipilimumab with Pexa-Vec in adults patients (pts) with solid tumors. The trial is conducted in pts with at least one injectable lesion (≥2 and ≤8 cm) and one distant non-injected measurable target site. Pts are treated with an IT injection of Pexa-Vec alone (1 x 109pfu) at Week 1 (W1) Day 1 (D1) followed by 3 IT injections of Pexa-Vec (1 x 109pfu) + ipilimumab (4 dose levels: 2.5, 5, 7.5, 10 mg/injection) at W3 D1, W5 D1 and W9 D1. Primary endpoint for escalation part is the occurrence of Dose Limiting Toxicities (DLT) defined as the toxicities occurring during the DLT assessment window (the first 5 weeks) related to Pexa-Vec, Ipilimumab or both; and the objective response rate as per immune related Response Criteria after 3 months of treatment for extension part. Secondary endpoints include the disease control rate, duration of response, progression free survival and overall survival. The dose escalation part follows a classical 3 + 3 design with 3 to 6 pts at each DL depending of the number of DTL observed (maximum of 24 pts). In the extension part, according to on the first stage of a Gehan design, 12 patients per cohort (3) will be enrolled (maximum of 36 pts). Up to date, the dose escalation part is ongoing: 8 pts were enrolled (DL1 n = 3; DL2 n = 3; DL3 n = 2).
Editorial acknowledgement
Bidaux As & Garin G; Centre Léon Bérard; DRCI Promotion Phase Précoce.
Clinical trial identification
EudraCT: 2014-001692-32; NCT02977156.
Legal entity responsible for the study
Centre Léon Bérard DRCI Promotion/Essais Précoces.
Funding
Centre Léon Bérard & Transgene S.A.
Disclosure
All authors have declared no conflicts of interest.
CD47-SIRPa directed therapies in (hemato) oncology (ID 70)
- J. Volkmer (Menlo Park, United States of America)
- J. Volkmer (Menlo Park, United States of America)
Session DOI (ID 513)
Immunotherapy for metastatic brain cancer (ID 98)
- A. Berghoff (Vienna, Austria)
- A. Berghoff (Vienna, Austria)