ACT with TIL is personalized immunotherapy with promising results in MM. Recently, the positive outcome of a multicenter (National Center for Cancer Immune Therapy [Herlev, DK] and the Netherlands Cancer Institute [Amsterdam, NL]) phase 3 trial evaluating TIL in MM patients (NCT02278887) was recently announced. In this trial, the objective response (OR) rate for TIL-treated patients was 49% with 20% obtaining a complete response according to RECIST 1.1. However, there are currently no validated biomarkers that correlate with response to TIL. Identifying cellular subsets associated with response to treatment could in the future help guide clinicians in treating MM patients with TIL.
In this study, we analyzed the cryopreserved samples of the TIL infusion product from all patients with unresectable stage IIIC-IV MM treated with TIL in the phase 3 trial using multiparametric flow cytometry. The phenotypic characteristics of the TIL infusion product and OR to therapy according to RECIST 1.1 were investigated. The Mann-Whitney U test was used to test unpaired observations for statistical significance.
In total, 80 patients received TIL, with 39 responders (complete + partial response) and 39 non-responders (stable + progressive disease). For 2 patients, the response was unevaluable. A higher number of TILs infused (Table) was significantly associated with response to therapy (p=0.013). Several lymphocyte subsets, including a higher number of CD8+ (p=0.004), CD8+CD28+ (p<0.001), CD8+BTLA+ (p=0.004), and CD8+CD39+ cells (p=0.007) favored response to therapy. Absolute number of cells infused (x109) Median (95 % confidence interval)
Subset Responders (n=39) Non-responders (n=39) p-value Total TIL 44.3 (38.4 - 51.2) 36.0 (29.6 - 43.5) 0.013 CD8+ 33.0 (22.9 - 36.8) 22.5 (15.8 - 26.1) 0.004 CD8+CD28+ 12.6 (9.5 - 15.6) 5.6 (4.0 - 9.1) <0.001 CD8+BTLA+ 6.8 (4.3 - 11.9) 3.0 (2.2 - 4.6) 0.004 CD8+CD39+ 29.3 (18.9 - 35.7) 20.8 (12.5 - 24.7) 0.007
In this study, we present an explorative immune characterization of the melanoma TIL infusion product and identify several cellular subsets that correlate with response to TIL therapy.
National Center for Cancer Immune Therapy (Herlev, DK) and the Netherlands Cancer Institute (Amsterdam, NL).
The trial was supported by the Dutch Cancer Society, the Netherlands Organization for Health Research and Development, the Dutch Ministry of Health, Stichting Avento, Copenhagen University Hospital, Herlev, the Danish Cancer Society and Capital Region of Denmark Research Foundation.
T. Holz Borch: Financial Interests, Personal, Other, Honorary lectoures: Bristol Meyer Squibb. M. Donia: Financial Interests, Personal, Invited Speaker, Teaching: Novartis, Roche; Financial Interests, Personal, Other, Advisor: Achilles Therapeutics; Non-Financial Interests, Personal, Other, Sub-investigator of clinical trial with connected translational research: Bristol Myers Squibb; Financial Interests, Personal, Proprietary Information, Proprietary Data Access: Bristol Myers Squibb; Other, Institutional, Other, Chariman of the Melanoma and non-melanoma Skin Cancer Scientific Committee: Danish Medicines Council (Medicinrådet). J.B.A.G. Haanen: Financial Interests, Institutional, Advisory Board: Bristol Myers Squibb, Achilles Therapeutics, Ipsen, Merck Sharpe & Dohme, Merck Serono, Pfizer, Molecular Partners, Novartis, Roche, Sanofi, Third Rock Venture, Iovance Biotherapeutics; Financial Interests, Institutional, Advisory Board, SAB member: BioNTech, Immunocore, Gadeta, Instil Bio, PokeAcel, T-Knife; Financial Interests, Personal, Advisory Board, SAB member: Neogene Therapeutics, Scenic; Financial Interests, Personal, Stocks/Shares: Neogene Therapeutics; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb, BioNTech US, Merck Sharpe & Dohme, Amgen, Novartis, Asher Bio; Non-Financial Interests, Personal, Member: ASCO, AACR, SITC; Other, Personal, Other, Editorial Board ESMO Open: ESMO; Other, Personal, Other, Editor-in-Chief IOTECH: ESMO; Other, Personal, Other, Editorial Board: Kidney Cancer. I. Svane: Financial Interests, Personal, Advisory Board: BMS, Pierre Fabre, Novartis; Financial Interests, Personal, Invited Speaker: MSD, Pierre Fabre, Novartis, Roche, BMS, MSD; Financial Interests, Personal, Stocks/Shares, Cofounder and Founder warrents: IO Biotech; Financial Interests, Institutional, Research Grant: Adaptimmune, Enara Bio, Lytix Biopharma, TILT Biotherapeutics; Financial Interests, Institutional, Funding: Evaxion; Non-Financial Interests, Personal, Principal Investigator: BMS, Roche, TILT Biotherapeutics, Lytix Biopharma, Novartis. All other authors have declared no conflicts of interest.