Browsing Over 268 Presentations
How rare are rare immune related Aes? (ID 28)
- R. Dummer (Zurich, Switzerland)
- R. Dummer (Zurich, Switzerland)
DOI session (ID 508)
Immunogenicity of neoepitopes (ID 60)
- D. Chowell (New York, United States of America)
- D. Chowell (New York, United States of America)
New checkpoints in the immunotherapy arena (ID 93)
- P. A. Ascierto (Napoli, Italy)
- P. A. Ascierto (Napoli, Italy)
Biomarkers (ID 233)
- K. M. Kerr (Aberdeen, United Kingdom)
- K. M. Kerr (Aberdeen, United Kingdom)
17P - The prognostic significance of androgen receptor phosphorylation and the immune infiltrate in prostate cancer (ID 392)
- H. GAN (Glasgow, United Kingdom)
- H. GAN (Glasgow, United Kingdom)
- M. McAllister (Glasgow, United Kingdom)
- V. Constancio (Glasgow, United Kingdom)
- S. Payne (Glasgow, United Kingdom)
- M. A. Underwood (Glasgow, United Kingdom)
- H. Y. Leung (Glasgow, United Kingdom)
- J. Edwards (Glasgow, United Kingdom)
Abstract
Background
The phosphorylation of the androgen receptor (AR) at various sites has been associated with diverse functions and clinical outcomes in prostate cancer and the processes underlying phosphorylation at S81 (pAR81) and S213 (pAR213) may possibly be targeted therapeutically. In addition, inflammation upregulates AR and cancer-promoting pathways, and high CD3+ and CD8+ T-cells in the tumour microenvironment have been associated with poorer outcomes. Therefore, this study aims to assess the prognostic value of tumour markers – AR, immune cell infiltrate and proliferation – and develop a combined prognostic score.
Methods
Immunohistochemistry was performed for 243 patients with prostate cancer to assess AR, pAR81, pAR213, Ki67, CD3 and CD8. AR expression was evaluated separately based on localisation: tumour or stromal cell, nuclear or cytoplasmic, with nuclear/cytoplasmic ratio (N/C) calculated. These tumour markers were assessed with overall survival and other biomarkers.
Results
High Ki67 (p = 0.003), CD8 (p = 0.022), CD3 (p = 0.006), and tumour cytoplasmic AR (p = 0.001) and pAR81 (p = 0.049), were associated with lower survival. Conversely, associated with higher survival were high tumour nuclear AR (p = 0.027) and N/C for AR (p = 3 × 10−4), pAR81(p = 0.032) and pAR213 (p = 0.010). In the stroma, high nuclear AR (p = 0.002), AR N/C (p = 0.041) and cytoplasmic pAR81 (p = 0.039) were associated with better survival. The Phosphorylated Androgen Receptor and Lymphocyte (PARL) score was derived by adding 1 for each of: high CD8, high tumour cytoplasmic pAR81, low tumour pAR213 N/C and low stromal nuclear AR. Patients are stratified into low (0-1), medium (2) and high (3-4) with worsening five-year survival of 88%, 79% and 50% respectively. The PARL score was a significant predictor of survival (p = 0.001), independent of Gleason score, prostate-specific antigen, perineural invasion and serum albumin.
Conclusions
CD3+ and CD8+ T-cell infiltration are negative prognostic markers, while the AR has different roles and prognostic values depending on localisation and phosphorylation. The PARL score could be a useful immunohistochemistry-based measure of tumour biomarkers for prognostication and adds value to current clinico-pathological markers.
Legal entity responsible for the study
NHS Greater Glasgow and Clyde.
Funding
Prostate Cancer UK Wolfson Foundation.
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.
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.
General discussion / Q&A (ID 19)
Clinical practice (including toxicities) (ID 499)
ImmunoPET detection of CD8 cytotoxic lymphocytes in immunotherapy (ID 51)
- A. Wu (Duarte, United States of America)
- A. Wu (Duarte, United States of America)