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Clinical Trial
. 2020 Aug;8(2):e000848.
doi: 10.1136/jitc-2020-000848.

Tumor infiltrating lymphocytes (TIL) therapy in metastatic melanoma: boosting of neoantigen-specific T cell reactivity and long-term follow-up

Joost H van den Berg  1 , Bianca Heemskerk  2 , Nienke van Rooij  2 , Raquel Gomez-Eerland  2 , Samira Michels  2 , Maaike van Zon  1 , Renate de Boer  1 , Noor A M Bakker  1 , Annelies Jorritsma-Smit  2 , Marit M van Buuren  2 , Pia Kvistborg  2 , Hergen Spits  3   4 , Remko Schotte  3 , Henk Mallo  5 , Matthias Karger  5 , Joris A van der Hage  6 , Michel W J M Wouters  7   8 , Loes M Pronk  9 , Marnix H Geukes Foppen  5 , Christian U Blank  10 , Jos H Beijnen  11   12 , Bastiaan Nuijen  11 , Ton N Schumacher  2   13 , John B A G Haanen  14
Affiliations
Clinical Trial

Tumor infiltrating lymphocytes (TIL) therapy in metastatic melanoma: boosting of neoantigen-specific T cell reactivity and long-term follow-up

Joost H van den Berg et al. J Immunother Cancer. 2020 Aug.

Abstract

Treatment of metastatic melanoma with autologous tumor infiltrating lymphocytes (TILs) is currently applied in several centers. Robust and remarkably consistent overall response rates, of around 50% of treated patients, have been observed across hospitals, including a substantial fraction of durable, complete responses.

Purpose: Execute a phase I/II feasibility study with TIL therapy in metastatic melanoma at the Netherlands Cancer Institute, with the goal to assess feasibility and potential value of a randomized phase III trial.

Experimental: Ten patients were treated with TIL therapy. Infusion products and peripheral blood samples were phenotypically characterized and neoantigen reactivity was assessed. Here, we present long-term clinical outcome and translational data on neoantigen reactivity of the T cell products.

Results: Five out of 10 patients, who were all anti-PD-1 naïve at time of treatment, showed an objective clinical response, including two patients with a complete response that are both ongoing for more than 7 years. Immune monitoring demonstrated that neoantigen-specific T cells were detectable in TIL infusion products from three out of three patients analyzed. For six out of the nine neoantigen-specific T cell responses detected in these TIL products, T cell response magnitude increased significantly in the peripheral blood compartment after therapy, and neoantigen-specific T cells were detectable for up to 3 years after TIL infusion.

Conclusion: The clinical results from this study confirm the robustness of TIL therapy in metastatic melanoma and the potential role of neoantigen-specific T cell reactivity. In addition, the data from this study supported the rationale to initiate an ongoing multicenter phase III TIL trial.

Keywords: immunotherapy, adoptive; lymphocytes, tumor-infiltrating; melanoma.

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Conflict of interest statement

Competing interests: JH has a research collaboration with BMS, MSD, Novartis and BionTech USA. JH serves as an advisor or consultant for: AIMM therapeutics, AZ, Amgen, Achilles TX, Bayer, BMS, GSK, Ipsen, Immunocore, MSD, Merck Serono, BionTech USA, Neogene Therapeutics, Novartis, Pfizer, Roche/Genentech, Sanofi, Seattle Genetics, Third Rock Ventures and Vaximm. TNS has a research collaboration with Merck KGaA. TNS serves as an adivisor or consultant for: Adaptive Biotechnologies, AIMM Therapeutics, Allogene Therapeutics, Merus, BionTech USA and Scenic Biotech. TNS is a stockholder of AIMM Therapeutics, Allogene Therapeutics, Merus, Neogene Therapeutics, BionTech USA and Scenic Biotech. AIMM Therapeutics holds IP to immortalize human B cells and the AT1412 antibody. HS and RS are employees of AIMM Therapeutics. RS and HS are stockholders of AIMM Therapeutics. The retroviral vectors containing BCL-6 and Bcl-xL have been generated by a for-profit company, AIMM Therapeutics, which makes the plasmids available. Obtaining the plasmids requires an MTA that includes financial obligations.

Figures

Figure 1
Figure 1
Clinical activity of TIL therapy (A) waterfall plot showing the best overall response for the 10 patients based on CT scans. (B) Photographic pictures of the upper leg of patient 3 who showed an impressive complete response on TIL therapy. The scar identifies the site of tumor resection for TIL isolation. This patient is currently tumor free for 9 years. TIL, tumor infiltrating lymphocyte.
Figure 2
Figure 2
Kinetics of neoantigen-specific CD8+ T cell responses in TIL responders Kinetics of neoantigen-specific CD8+ T cell responses in peripheral blood of patient 3 (A), 4 (B) and 8 (C). T cell responses against the indicated epitopes were first identified in infusion products by MHC multimer screening and subsequently followed in peripheral blood using the same technology. HC, major histocompatibility complex; TIL, tumor infiltrating lymphocyte.
See this image and copyright information in PMC

References

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