SINGAPORE – February 08, 2021 – Lion TCR announces abstracts presentation at the European Association for the Study of the Liver (EASL) Digital Liver Cancer Summit 2021 on 05-06 February 2021 for the use of its lead T-cell product, LioCyx-M for the treatment of unresectable Hepatitis B virus (HBV)- related hepatocellular carcinoma (HCC) in a Phase 1 study (NCT03899415), with an oral abstract (O07) selected for Highlights in the Best of Liver Cancer Summit.

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We have previously presented clinical data for this study at the 2020 Society for Immunotherapy of Cancer (SITC) Annual Meeting, highlighting the use of LioCyx-M as a promising TCR-T immunotherapy for primary HCC. Here, we present an updated clinical data (poster abstract P065), with supporting biomarker analysis data (oral abstract O07).

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The median overall survival was 33.57 months with a follow-up period of 47.9 months and an objective response rate of 16.7%, as compared to a median OS of 10.7 months achieved by FDA-approved first-line drug sorafenib (Llovet et al, N Engl J Med, 2008). LioCyx-M infusions were well tolerated with no cytokine release syndrome (CRS), neurotoxicity or other systemic immune-related adverse events observed. Two patients had a self-limiting and localized liver inflammation upon infusion of 1x10E05 cells/kg per bodyweight that fully resolved despite the advanced pathological liver condition of the patient.

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A total of 3 patients had elevations of serum chemokines and/or activation of the T cell compartment upon receiving the treatment, indicative of treatment induced immunological alterations. These alterations were followed with subsequent tumour destruction (partial response as per modified RECIST) in one patient with a durable tumour response lasting approximately 30 months, or a stable disease in the other 2, implicating the LioCyx-M treatment induced immunological alterations with anti-tumour response.

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Overall, the clinical and biomarker data highlight the good safety profile and efficacy of LioCyx-M. Further exploration of efficacy of LioCyx-M treatment for advanced HBV-HCC is warranted in a Phase 2 study. Lion TCR is actively applying for global multi-center Phase II clinical trials, including the US FDA, Singapore HSA and China NMPA.

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Details of oral presentation:

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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Details of poster presentation:

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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The full abstracts are attached in this release and will be published in The Digital Liver Cancer Summit 2021 abstract book on 22 January at 10:00 CET.

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Abstract O07 has been chosen to be highlighted in the Best of Liver Cancer Summit.

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About Lion TCR
Lion TCR is a Singapore based clinical-stage biotechnology company, focused on the development of T cell receptor (TCR)-T cell therapy against life-threatening viral infections and viral-related cancers pertinent in Asia.‍

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About LioCyx-M
LioCyx-M, including several well-established product derivatives, are autologous T cells modified to express HBV-specific TCR. These modified T cells have been shown to be able to lyse HBV-infected HCC cells upon target recognition in in vivo pre-clinical studies and in patients (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

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