Browsing Over 268 Presentations
DOI (ID 503)
Immune therapeutics in gastric and colorectal cancer (ID 88)
- J. Tabernero (Barcelona, Spain)
- J. Tabernero (Barcelona, Spain)
32O - Successful use of interferon-alpha and adoptive T cell therapy for metastatic melanoma patients failing other treatment options (ID 277)
- M. K. Van der Kooij (Leiden, Netherlands)
- M. K. Van der Kooij (Leiden, Netherlands)
- E. Verdegaal (Leiden, Netherlands)
- M. Visser (Leiden, Netherlands)
- L. De Bruin (Leiden, Netherlands)
- C. Van der Minne (Leiden, Netherlands)
- S. J. Santegoets (Leiden, Netherlands)
- M. J. Welters (Leiden, Netherlands)
- J. B. Haanen (Amsterdam, Netherlands)
- E. Kapiteijn (Leiden, Netherlands)
- S. H. Van der Burg (Leiden, Netherlands)
Abstract
Background
Current standard-of-care immunotherapies target the interaction between tumor and T cells. However, frequently there are insufficient numbers of tumor-specific T cells present. Hence, these patients may benefit from adoptive cell transfer (ACT) with melanoma-specific T cells. The general conditioning and maintenance treatment for ACT consists of lymphodepleting chemotherapy with or without total body irradiation, and post-transfusion high-dose IL-2. In our hospital we replaced this rather toxic treatment scheme with low-dose interferon-alpha (IFNa).
Methods
Twenty-four patients with progressive metastatic melanoma received up to three infusions with ex vivo expanded tumor infiltrating lymphocytes (TIL) every three weeks, ranging between 1-10 x 108 T cells per infusion. One week before the first TIL infusion patients started with daily subcutaneous IFNa injections. These injections were continued for eleven weeks as a maintenance treatment. Total blood count was measured before the start of IFNa, and before each TIL infusion. Furthermore, serum and PBMC were collected at these time-points. Twelve weeks after the first TIL infusion the patients received a radiological response evaluation.
Results
The combination of IFNa and ACT is safe and well tolerated. IFNa causes a mild lymphopenia, neutropenia and leukopenia. Both responders and non-responders show a decrease in these blood counts after one week of IFNa. Strikingly, persistence of leukopenia and in particular neutropenia predicts the response to TIL therapy. Furthermore, high leukocyte/lymphocyte and platelet/lymphocyte ratios are predictive biomarkers for response to treatment. Clinical benefit was seen in 7 out of 24 (29%) patients with stable disease for an average of 36 weeks. Although nineteen patients failed extensive pre-treatment with BRAF/MEK inhibitor and/or anti-PD1 and/or anti-CTLA4, five of them still displayed stabilization of disease (26.3%) after ACT.
Conclusions
The persistence of leukopenia induced by low-dose IFNa is a predictor of response to TIL therapy. Furthermore, this treatment combination is a viable option for heavily pre-treated metastatic melanoma patients.
Clinical trial identification
Local Ethics Committee P04.085.
Legal entity responsible for the study
Medical Oncology, Leiden University Medical Center.
Funding
KWF (Dutch Cancer Society).
Disclosure
E.M.E. Verdegaal: In relation to research: Affiliations or financial involvement: ISA pharmaceuticals B.V., AIMM Therapeutics, PamGene. J.B.A.G. Haanen: Advisory boards, consultation and lectures: Pfizer, Bayer, MSD, BMS, Ipsen, Novartis, Roche/Genentech, Neon Therapeutics, Celsius Therapeutics, Gadeta BV, Immunocore. Grants to NKI: BMS, MSD, Novartis, Neon Therapeutics. E. Kapiteijn: Advisory boards: Roche, BMS, MSD, Novarits, Pierre-Fabre, Genzyme-Sanofi, Eisai, Servier, Sirtex, Delcath (for which LUMC received honoraria). Grant support to LUMC: Novartis, BMS. S.H. van der Burg: Advisory boards: ISA Pharmaceuticals B.V., PCI-Biotech, IO-Biotech; Corporate grant support: Innate Pharma, Kite Pharma EU B.V., AIMM Therapeutics; Service agreements: ISA Pharmaceuticals B.B., IO Biotech. All other authors have declared no conflicts of interest.
22P - PD-L1 microSPECT/CT imaging for longitudinal monitoring of PD-L1 expression in syngeneic and humanized mouse models for cancer (ID 348)
- S. Heskamp (Nijmegen, Netherlands)
- S. Heskamp (Nijmegen, Netherlands)
- S. R. Verhoeff (Nijmegen, Netherlands)
- P. J. Wierstra (Nijmegen, Netherlands)
- J. D. Molkenboer-Kuenen (Nijmegen, Netherlands)
- G. W. Sandker (Nijmegen, Netherlands)
- S. Thordardottir (Nijmegen, Netherlands)
- D. Olive (Marseille, France)
- J. Bussink (Nijmegen, Netherlands)
- O. C. Boerman (Nijmegen, Netherlands)
- H. Dolstra (Nijmegen, Netherlands)
- E. H. Aarntzen (Nijmegen, Netherlands)
- W. A. Hobo (Nijmegen, Netherlands)
Abstract
Background
Antibodies that block the interaction between programmed death ligand 1 (PD-L1) and PD-1 have shown impressive responses in subgroups of cancer patient. PD-L1 expression in the tumor seems to be a pre-requisite for treatment response. However, it is heterogeneously expressed within tumor lesions and may change upon disease progression and treatment. Imaging of PD-L1 could aid in patient selection.
Methods
Previously, we showed the feasibility to image PD-L1 positive tumors in immunodeficient mice. However, PD-L1 is also expressed on immune cell subsets. Therefore, the aim of this study was to assess the potential of PD-L1 microSPECT/CT using radiolabeled anti-PD-L1 antibodies to 1) measure PD-L1 expression in two immunocompetent tumor models (syngeneic mice and humanized mice harboring PD-L1 expressing immune cells) and 2) monitor therapy induced changes in tumor PD-L1 expression levels.
Results
We showed that radiolabeled anti-PD-L1 antibodies accumulated preferentially in PD-L1 positive tumors, despite considerable uptake in certain normal lymphoid tissues (spleen and lymph nodes) and non-lymphoid tissues (duodenum and brown fat). Moreover, PD-L1 microSPECT/CT imaging could distinguish between high and low PD-L1 expressing tumors. Notably, presence of PD-L1 positive immune cells did not compromise tumor uptake of the anti-human PD-L1 antibodies in humanized mice. Most importantly, we demonstrated that radiotherapy induced up-regulation of PD-L1 expression in murine tumors which could be monitored with microSPECT/CT imaging.
Conclusions
Together, these data demonstrate that PD-L1 microSPECT/CT is a sensitive technique to detect varying levels of tumor PD-L1 expression and in the future, this technique may enable patient selection for PD-1/PD-L1 targeted therapy.
Legal entity responsible for the study
Radboud UMC.
Funding
Netherlands Organisation for Scientific Research and Dutch Cancer Society.
Disclosure
All authors have declared no conflicts of interest.
56P - Evaluating safety and efficacy of immune checkpoint inhibitors (ICI) in elderly patients (pts) for advanced cancer treatment: A retrospective study (ID 261)
- S. J. Brixius (Freiburg, Germany)
- S. J. Brixius (Freiburg, Germany)
- F. Meiss (Freiburg, Germany)
- D. Von Bubnoff (Freiburg, Germany)
- R. Zeiser (Freiburg, Germany)
- C. F. Waller (Freiburg, Germany)
- J. Duyster (Freiburg, Germany)
- J. Rawluk (Freiburg, Germany)
Abstract
Background
Older pts with cancer require special consideration with respect to cancer treatment due to multiple comorbidities and an altered immune status. However, older pts are often under-represented in clinical trials, so information about the use of ICIs in elderly pts is marginal.
Methods
We retrospectively identified cancer pts aged over 70 yrs treated with any ICI between 04/2012 and 04/2018. Tumor entities, laboratory parameters, steroid use, adverse events (AE) as well as survival and therapy data were compared.
Results
176 pts were included (120 M, 56 F), the median age was 75 yrs (range 70-89) with 89 pts aged 75 or younger (%) and 87 pts over 75 (%). 38 pts (22%) had ECOG 0, 100 pts (57%) had ECOG 1, 23 pts had ECOG 2-3 (13%), in 15 pts (8%) data was not available. 175 pts (99%) had preexisting medical problems. Assessed by the Cumulative Illness Rating Scale for Geriatrics (CIRS-G), 100 pts (57%) had severe comorbidities in at least one, 43 pts (24%) in at least two organ systems. 76 pts (43%) had no severe comorbidities. 89 pts (51%) had malignant melanoma, 62 (35%) non-small cell lung cancer and 8 (5%) renal-cell carcinoma. 155 pts (93%) were in a metastasized stage. 81 pts (46%) received pembrolizumab, 72 (41%) nivolumab, 35 (20%) ipilimumab, 3 (2%) atezolizumab, 1 (0.6%) durvalumab and azacitidin and 6 pts (3%) were treated with a combination of anti-PD(L)1- and anti-CTLA4-antibodies. 19pts (11%) received various consecutive ICIs. An average immunotherapy consisted of 10.2 doses (range 1-52 doses) and took 6.5 months (range 1 day – 3.9 yrs). 152 pts (86%) had AEs. 59 (34%) had severe AEs (CTCAE grad 3-4) and 63 pts (36%) required systemic corticosteroids due to AEs. We observed common described immune related AEs in 82 pts (47%). Therapy discontinuations due to AEs were in 35 pts (20%), in 23 pts (13%) the ICI was definitely stopped. We note a disease control rate (DCR) of 60% (21pts CR; 60pts PR, 67 pts SD) in the follow-up CT scans. The median survival under ICI was 11.8 months (range 5 days – 4.6 yrs).
Conclusions
Our data encourage that the use of ICI in elderly is beneficial even though AEs are commonly reported and potentially harmful.
Legal entity responsible for the study
Department of Hematology, Oncology and Stem Cell Transplantation, Freiburg University Medical Center, Freiburg, Germany.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
General discussion / Q&A (ID 19)
91P - A dual-targeting fusion protein, human PVR-4-1BBL for immunotherapy in AML (ID 227)
- H. Park (Gyeonggi, Korea, Republic of)
- H. Park (Gyeonggi, Korea, Republic of)
- H. Nam (Youngin-si, Korea, Republic of)
- H. Kwon (Youngin-si, Korea, Republic of)
- C. Yu (Youngin-si, Korea, Republic of)
- S. Song (Youngin-si, Korea, Republic of)
- I. Oh (Youngin-si, Korea, Republic of)
- H. Yang (Youngin-si, Korea, Republic of)
- E. Jo (Youngin-si, Korea, Republic of)
- J. Won (Youngin-si, Korea, Republic of)
- S. Eun (Youngin-si, Korea, Republic of)
Abstract
Background
4-1BB (CD137; TNFRSF9) binds 4-1BBL, which triggers subsequent proliferation and activation of immune cells, T and NK cells in particular. We designed and generated PVR-4-1BBL, a hexameric protein of 4-1BBL fused to PVR (CD155), the major ligand for TIGIT that marks exhausted T cells. This fusion protein efficiently bind to its targets TIGIT and 4-1BB on cells as well as in soluble form.
Methods
To evaluate the in vitro efficacy of PVR-4-1BBL, T cells were isolated from PBMCs of healthy individuals or AML patients and then stimulated with anti-CD3 alone or in combination with PVR-4-1BBL. The percentages and numbers of CD25+CD69+ T cells were measured by flow cytometry. Secreted INF-γ and TNF-α were measured by ELISA. In order to test the activity of 4-1BB signaling induced by the fusion protein, we performed 4-1BB-stimulated- NFκB reporter assay.
Results
As a result, PVR-4-1BBL activated human T cell to induce cellular proliferation and activation as well as production of cytokines, such as INF-γ and TNF-α. The fusion protein increased T cell activation particularly under suboptimal conditions of TCR stimulation. Functional activity of this fusion protein on 4-1BB-mediated cellular NF-κB signaling was more potent than a 4-1BB agonist antibody in the presence of TIGIT-positive cells in close proximity. Our fusion protein showed target-specific potency in T cell activation in the presence of both TIGIT and 4-1BB. Therefore it is expected to have a lower side effect than 4-1BB agonist antibody which may affect peripheral T cells. According to a recent report, TIGIT was up-regulated on CD8+ T cells of AML patients. We confirmed that 4-1BB was also induced in T cells from AML patients’ PBMCs along with TIGIT when stimulated by anti-CD3. The fusion protein increased T cell activation and IFN-γ production much more than agonistic anti-4-1BB antibody in AML patients’ PBMCs.
Conclusions
In conclusion, PVR-4-1BBL confers a dual targeting function, effectively enhancing T cell proliferation, activation and cytokine production. Therefore, we propose that the dual-targeting fusion protein, PVR-4-1BBL is a promising drug candidate for AML treatment designed by a novel immunotherapeutic approach.
Legal entity responsible for the study
MOGAM Institute for Biomedical Research.
Funding
MOGAM Institute for Biomedical Research.
Disclosure
All authors have declared no conflicts of interest.
ImmunoPET detection of CD8 cytotoxic lymphocytes in immunotherapy (ID 51)
- A. Wu (Duarte, United States of America)
- A. Wu (Duarte, United States of America)
Clinical practice (including toxicities) (ID 499)
Vaccine and EBV targeting IO strategies (ID 83)
- N. M. Steven (Birmingham, West Midlands, United Kingdom)
- N. M. Steven (Birmingham, West Midlands, United Kingdom)
Presentation 1 (ID 531)
Biomarkers (ID 233)
- K. M. Kerr (Aberdeen, United Kingdom)
- K. M. Kerr (Aberdeen, United Kingdom)