新加坡–2021年2月8日–来恩于2021年2月5至6日举办的欧洲肝脏协会(EASL)数字肝癌峰会上发表了摘要，介绍其龙头TCR-T细胞产品LioCyx-M在一项临床1期研究（NCT03899415）中，用于治疗手术不可切除的乙型肝炎病毒（HBV）相关的肝细胞癌（HCC）的更新临床数据。来恩的摘要演讲 (O07) 被选为肝癌峰会的亮点。
Abstract Title: Immunological alterations induced by HBV-TCR T cell immunotherapy associates with treatment response of primary HBV related-HCC
Presenter Name: Dr Tan Anthony Tanoto
Abstract Number: O07
Abstract Title: Phase 1 study of autologous hepatitis B virus (HBV)-specific T cell receptor (TCR) T-cells, LioCyx-M in unresectable HBV-related hepatocellular carcinoma (HCC)
Presenter Name: Prof Fu-Sheng Wang
Abstract Number: P065
LioCyx-M是经过修饰可表达乙肝病毒特异性T细胞受体的自体T细胞。临床前研究和临床研究数据显示，这些经过修饰的T细胞能够标识并且裂解乙肝病毒感染的肝癌细胞。 (Koh et al, Mol. Ther. Nucleic Acids, 2013; Kah et al, J. Clin. Invest., 2017; Tan et al, Gastroenterology 2019).
Abstract no: O07
Immunological alterations induced by HBV-TCR T cell immunotherapy associates with treatment response of primary HBV related-HCC
Anthony Tan, Jiehua Jin, Jinfang Zhao, Fanping Meng, Alicia Chua, Zi Zong Ho, Lu-En Wai, Sarene Koh, Antonio Bertoletti, Fu-sheng Wang
Background and Aims: The application of HBV-TCR T cell immunotherapy in chronic HBV patients with primary HCC have been somewhat apathetic due to the increased risk of on-target off-tumour severe liver inflammatory events. However, such immunological changes after T cell immunotherapy could also indicate a less compromised immune system that can better respond to treatment. Here we longitudinally analysed the immunological, virological, biochemical and radiological alterations in primary HBV-HCC patients receiving HBV-TCR T cell immunotherapy to determine its association with treatment response.
Method: Patients (n=8) with diffuse non-operable HBV-associated HCC was scheduled to receive escalating doses (1×10^4, 1×10^5, 1×10^6, 5×10^6 / kg body weight) of mRNA electroporated HBV-TCR T cells at weekly intervals. Serum and PBMCs were collected at baseline and at regular intervals post T cell infusion to monitor for liver inflammation and the quantity of cytokines and the frequency and activation phenotype of T cells were analysed respectively. Treatment response was evaluated primarily by radiological imaging or by the detection of serum HBV pgRNA as a surrogate.
Results: 2 patients exhibited signs of reversible liver inflammation after receiving the second dose of HBV TCR T cells (1×10^5 / kg body weight, ~6×10^6 HBV-TCR T cells in total). In one, this is accompanied with the elevation of total bilirubin and clinical symptoms of nausea and jaundice (pt. 1), while the other did not (pt. 2). Interestingly, the peak liver inflammation in pt. 1 coincided with an elevation of activated T cell frequency in the peripheral blood (~20 days post treatment) which was followed by a dramatic destruction of the tumour lesion. While radiological response was not observed in pt. 2, we detected a decline in serum HBV pgRNA levels upon treatment, indicative of a functional HBV-TCR T cell treatment. In two patients with elevations of serum CXCL-9 and CXCL-10, or a detectable increase in activated T cell frequency in the peripheral blood after receiving high doses of HBV-TCR T cells (5×106 / kg), the tumour load remained stable throughout treatment, while in those with no detectable peripheral blood alterations, tumour load continued to increase.
Conclusion: Immunological alterations in the peripheral blood induced by T cell immunotherapy is associated with treatment response. This has important implications in the monitoring of primary HBV-HCC patients receiving T cell immunotherapy.
Abstract no: P065
Phase 1 study of autologous hepatitis B virus (HBV)-specific T cell receptor (TCR) T-cells, LioCyx-M in unresectable HBV-related hepatocellular carcinoma (HCC)
Fu-Sheng Wang1*, Fanping Meng1, Jiehua Jin 1, Yuanyuan Li 1, Regina Wanju Wong2, Anthony Tanoto Tan3, Tingting Wang2, Antonio Bertoletti2,3,4*
1Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, China. 2Lion TCR Pte Ltd, Singapore 3Emerging Infectious Diseases, Duke-NUS Medical School, Singapore 4Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore (*co-corresponding author)
Background and Aims: LioCyx-M is an autologous T cell product transiently modified with in-vitro transcribed mRNA encoding Hepatitis-B-virus (HBV)-specific T cell receptor (TCR). The transient TCR expression allows for a conservative dose escalation to closely monitor for potential toxicities. Here, we assessed the safety and tolerability of LioCyx-M in patients with unresectable HBV-related hepatocellular carcinoma (HCC) without curative treatment options.
Method: Eligible patients had matched HLA class I and BCLC B or C HCC (Child-Pugh < 7 points). The treatment regimen consists of 2 treatment cycles. Treatment Cycle 1 consists of 4 weekly escalating doses of 1x10E04 cells/kg, 1x10E05 cells/kg, 1x10E06 cells/kg, 5x10E06 cells/kg bodyweight (BW). This is followed by a 1-month safety assessment according to NCI CTCAE V4.0.3. If there were no dose associated toxicities, patients were eligible to receive Treatment Cycle 2 consisting four weekly infusions at dose of 5 x10E06 cells/kg BW. Tumor response per RECIST 1.1 criteria and survival time were assessed.
Results: As of data cutoff on 30 April 2020, 8 patients of a median age of 53 (range: 49 – 67) were enrolled. A median number of 6 (range: 4 – 12) infusions were administrated to each patient. Of the 7 patients evaluable for tumour response, 3 patients showed stable disease with ≥ 3 months duration (range: 3.0 – 9.5 months) as per RECIST criteria 1.1. A remarkable reduction in the size of liver tumor of > 30% which maintained for 30 months was observed in one patient (Please see Figure). Notably, this tumour shrinkage was accompanied by transient Grade 3 elevations in ALT, GGT, AST and bilirubin after receiving second dose of LioCyx-M at dose level of 1x10E05 cells/kg BW, indicating the on-target effects of LioCyx-M. Grade 1 transient fever was reported in another patient after receiving 4th, 5th and 6th infusions at dose level 5x10E06 cells/kg BW. There were no treatment-related adverse events such as cytokine release syndrome or neurotoxicity. Median time to progression was 2.97 months (90% CI: 0.23 – 9.53 months). Median overall survival was 33.57 months (90% CI: 2.53 months – NA). Four patients were alive at data cutoff.
Conclusion: Our data have demonstrated the on-target ability of LioCyx-M with promising clinical outcome and good safety profile. Further efficacy exploration of LioCyx-M for advanced HBV-HCC is required in a Phase 2 study. Funding: Lion TCR. Clinical trial information: NCT03899415
来恩生物科学创始人Antonio Bertoletti 教授被委任为 Singhealth Duke-NUS 细胞治疗中心 (Singhealth Duke-NUS Cell Therapy Centre, SDCT) 细胞免疫用于传染病方向的负责人