A Novel Affinity-Enhanced NY-ESO-1-Targeting TCR-Redirected T cell Transfer Exhibiting Early-Onset Cytokine Release Syndrome and Subsequent Tumour Responses in Synovial Sarcoma Patients - European Medical Journal
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A Novel Affinity-Enhanced NY-ESO-1-Targeting TCR-Redirected T cell Transfer Exhibiting Early-Onset Cytokine Release Syndrome and Subsequent Tumour Responses in Synovial Sarcoma Patients

Authors:
Hiroyoshi Hattori,1 Mikiya Ishihara,2 Shigehisa Kitano,3 Yoshihiro Miyahara,2 Hidefumi Kato,4 Hideyuki Mishima,4 Noboru Yamamoto,3 Takeru Funakoshi,5 Takashi Kojima,6 Tetsuro Sasada,7 Eiichi Sato,8 Sachiko Okamoto,9 Daisuke Tomura,9 Hideto Chono,9 Ikuei Nukaya,9 Junichi Mineno,9 Hiroaki Ikeda,10 Takashi Watanabe,2 Shinichi Kageyama,2 Hiroshi Shiku2
Disclosure:

Dr Ishihara has received personal fees from Chugai, Eisai, MSD, Pfizer, and Takara Bio. Dr Yamamoto has received grants from Astellas, Bayer, BMS, Boehringer Ingelheim, Chugai, Daiichi-Sankyo, Eisai, Janssen Pharma, Kyowa-Hakko Kirin, Lilly, Merck, Novartis, Pfizer, Quintiles, and Taiho; and personal fees from AstraZeneca, BMS, Boehringer Ingelheim, Chugai, Cimic, Eisai, Lilly, Ono Pharmaceutical Co. Ltd., Otsuka, Takeda, Pfizer, and Sysmex. Dr Kojima has received grants from Astellas Amgen BioPharma, Chugaiseiyaku, MSD, Oncolys BioPharma, Ono Pharmaceutical Co. Ltd., Paraxel, and Sihonogi. Dr Sasada has received grants from AMED, BrightPath Biotherapeutics Co. Ltd., JSPS, and Taiho; and personal fees from Bristol-Myers Squibb, Chugai, Nippon Kayaku, and Ono Pharmaceutical Co. Ltd. Dr Okamoto, Dr Tomura, Dr Chono, Dr Nukaya, and Dr Mineno have received grants from AMED and personal fees from TakaraBio Inc. Dr Ikeda has received grants from Takara Bio Inc. Dr Watanabe has received personal fees from AstraZeneca, Bristol-Meyers Squibb, and Chugai; and has funding source to support Dept. of Immuno-Gene Therapy in Mie Univ. from TakaraBio Inc. and United Immunity Inc. Dr Skiku has received grants from TakaraBio Inc. and licensed patents from Virus Vector.

Acknowledgements:

The authors are grateful to members of TakaraBio Inc. for the preparation of TCR-T-cells and the analysis of the cell kinetics, and also to members of Takara Bio Inc. and FiveRings Co. for their support to the clinical trial management. This research was supported by the Medical Research and Development Programs Focused on Technology Transfer, Adaptable and Seamless Technology Transfer Program Through Target-driven R&D (A-STEP) from Japan Agency for Medical Research and development (AMED).

Citation
EMJ Oncol.. ;7[1]:38-40. Abstract No AR01.

Each article is made available under the terms of the Creative Commons Attribution-Non Commercial 4.0 License.

BACKGROUND

Adoptive transfer of T cell receptor (TCR)-redirected T cells has been reported to exhibit efficacy in some patients with melanoma and sarcoma.1 However, cytokine release syndrome (CRS) and its relation to tumour response has not been well-documented. This study aimed to evaluate clinical responses in association with the cell kinetics and CRS after transfer of high-affinity NY-ESO-1 TCR-gene transduced T cells in cancer patients.2

METHODS

The authors developed a novel-type affinity-enhanced NY-ESO-1-specific TCR and an originally-developed retrovirus vector that encodes small interfering RNA (siRNA) to silence endogenous TCR creation.3 The NY-ESO-1/TCR sequence was mutated for high affinity with replacements of G50A and A51E in the CDR2 region.4 This was a first-in-human clinical trial of the novel NY-ESO-1-specfic TCR-T cell transfer to evaluate the safety, in vivo cell kinetics, and clinical responses. It was designed as a cell-dose escalation from 5×108 (cohort 1) to 5×109 (cohort 2) cells. NY-ESO-1-expressing refractory cancer patients were enrolled with a 3+3 cohort design. Eligibility criteria included being ≥20 years of age, recurrent/refractory tumour, NY-ESO-1 positive expression in the tumour specimen, HLA-A*02:01 or *02:06 (+) for NY-ESO-1, and informed consent. A 200 mL blood draw from each patient was obtained. TCR-gene transduction and culture were carried out for 10–12 days, followed by deep freezing quality check. Cyclophosphamide (1,500 mg/m2) was administered prior to the TCR-T cell transfer as preconditioning.

RESULTS

Nine patients were treated with the TCR-T cells that expanded in peripheral blood with a dose-dependent manner, associated with rapid proliferation within 5 days of infusion. Three patients receiving 5×109 cells developed early-onset CRS, with elevated levels of serum IL-6 and IFN-γ. These CRS on Day 1 or 2 were well managed with tocilizumab treatment. Three synovial sarcoma patients exhibited tumour shrinkage and partial responses, and they all had high-expression of NY-ESO-1 in the tumour samples, namely 75% or more (Table 1). Intriguingly, tumour regrowth seemed to be inversely correlated with a steep decrease in the number of the TCR-gene-transduced lymphocytes after the TCR-T therapy, especially in the patient with high tumour burden, such as TBI1301-16. Exploratory analysis revealed that multiple chemotactic cytokines, including CCL2 and CCL7, as well as IL-3 increased in the serum of patients with CRS. The proportions of effector-memory phenotype T cells in the infused cell-product were significantly associated with CRS development.

Table 1: Patients’ characteristics who received adoptive transfer of TBI-1301.
*Tocilizumab was used to treat CRS. **Cases without measurable lesions.
CRS: cytokine release syndrome; PD: progressive disease; PR: partial response; SD: stable disease.

CONCLUSION

The affinity-enhanced NY-ESO-1/TCR-T cell transfer exhibited early-onset CRS in association with in vivo cell proliferation and sequential tumour responses in the patients with high-NY-ESO-1-expressing synovial sarcoma. Further understanding and development of the TCR-T therapies are needed to increase the ability to overcome the challenges of treating solid tumours, such as high tumour burden patients.

References
Robbins PF et al. Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J Clin Oncol. 2011;29(7):917-24. Mie University. Investigator initiated Phase 1 study of TBI-1301. NCT02366546. Available at: https://clinicaltrials.gov/ct2/show/NCT02366546. Okamoto S et al. Improved expression and reactivity of transduced tumor-specific TCRs in human lymphocytes by specific silencing of endogenous TCR. Cancer Res. 2009;69(23):9003-11. Schmid DA et al. Evidence for a TCR affinity threshold delimiting maximal CD8 T cell function. J Immunol. 2010;184(9):4936-46.