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。

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来恩先前已在2020年国际癌症免疫疗法学会（SITC）的年会上介绍了该研究的临床数据，强调了LioCyx-M是极具前景的针对原发性肝癌的TCR-T免疫疗法。在此，我们提供了经过更新的临床数据（海报摘要P065），以及相关生物标记物分析数据（口头报告摘要O07）。

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临床病人的随访期为47.9个月，中位总生存期为33.57个月，客观缓解率为16.7％。 目前FDA批准的一线药物索拉非尼的中位总生存期为10.7个月。病人对于LioCyx-M输注的耐受性良好，无细胞因子释放综合征（CRS），神经毒性或其他全身性免疫系统相关的不良反应。在接受了剂量为每公斤体重1X10E05个TCR-T细胞的LioCyx-M输注后，有2名患者出现了自限性和局部的肝脏炎性反应。尽管这两名患者的肝脏呈现晚期的病理性病变，这两名患者的不良反应均得到了完全的恢复。

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共有3名患者在接受治疗后表现出血清趋化因子升高和/或T细胞激活，表明治疗引起了病人免疫学的改变。这些改变发生之后，一名患者的肿瘤被破坏（根据修订版 RECIST规范定义为部分缓解），该患者展示出了约30个月的持久性肿瘤应答。另两名患者的疾病稳定。这些临床数据表明LioCyx-M治疗诱导了免疫学的改变并引起了抗肿瘤反应。

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总的来说，临床和生物标志物数据展示出了LioCyx-M良好的安全性及疗效。在稍后的临床二期研究中，我们将进一步探索LioCyx-M疗法对于晚期HBV-HCC的疗效。来恩目前正在积极申报全球多中心二期临床包含美国FDA、新加坡HSA以及中国的NMPA。

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口头演讲详情如下:

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

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海报演示详情如下:

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

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本新闻稿随附完整摘要。所附摘要将于2021年1月22日欧洲中部时间上午10点整发布在2021年数字肝癌峰会的摘要录中。

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摘要O07已被选为肝癌峰会的亮点。

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来恩生物医药有限公司简介
来恩生物医药有限公司是一家总部位于新加坡，处于临床研发阶段的生物科技公司，致力于开发T细胞受体（TCR）- T细胞疗法，以治疗亚洲地区广泛流行的危及生命的病毒感染和病毒感染导致的癌症。

龙头产品LioCyx-M简介
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).

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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

Email: anthony.tan@duke-nus.edu.sg

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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.

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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.

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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.

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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.

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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)

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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.

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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.

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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.

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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