Safety and clinical improvement in a phase I trial of autologous Epstein–Barr virus-specific T cell therapy in patients with progressive multiple sclerosis
ECTRIMS Online Library. Pender M. 10/26/17; 200440; P785
Michael Pender
Michael Pender
Contributions
Abstract

Abstract: P785

Type: Poster

Abstract Category: Therapy - disease modifying - 31 Treatment of progressive MS

Background: Increasing evidence indicates a role for Epstein-Barr virus (EBV) infection in the pathogenesis of multiple sclerosis (MS). EBV-infected autoreactive B cells might accumulate in the central nervous system because of defective cytotoxic CD8+ T cell immunity.
Objective: To determine the safety of treating progressive MS patients with autologous EBV-specific T-cells.
Methods: This 26 week phase I trial is designed to treat 5 patients with secondary progressive MS (SPMS) and 5 patients with primary progressive MS (PPMS) with autologous EBV-specific T cells targeting EBV nuclear antigen-1, latent membrane protein 1 (LMP1) and LMP2A. Four escalating doses are administered biweekly.
Results: To date (May 2017), 8 patients (5 SPMS and 3 PPMS) have received the full course of therapy, including one SPMS patient who had been treated 4 years earlier (compassionate use) and was treated on study owing to worsening symptoms after 3.5 years of sustained improvement. Five of these patients have experienced clinical improvements. Exploratory analyses suggest that clinical improvement correlates with the levels of EBV-specific reactivity and polyfunctionality (IFNγ/TNFα/IL2/CD107a expression) of the administered CD8+ T cells. No significant adverse events have been observed. One treatment-related adverse event, transient grade 1 dysgeusia likely related to DMSO, was observed. Of the first six patients, three experienced symptomatic and objective clinical improvement, commencing 2-8 weeks after the first infusion. Marked improvement occurred in one SPMS patient, with resolution of fatigue, increased manual dexterity, increased walking distance and improvement in lower limb tone, power, reflexes, sensation and coordination. A second SPMS patient had reduced fatigue, increased productivity and improved balance. A third patient (PPMS) had improved colour vision, visual acuity and manual dexterity and reduced fatigue, lower limb spasms and urinary urgency. The seventh (PPMS) and eight (SPMS) patients were most recently assessed at 6 weeks following their first T cell infusion and reported reduced fatigue and improved cognition. The ninth patient (PPMS) has so far received one T cell infusion.
Conclusion: Our findings, to date, of safety and clinical improvement set the stage for further clinical trials with autologous and allogeneic EBV-targeted T cell therapy in MS. Updated data for all 10 patients will be presented at the meeting.
Disclosure:
Michael Pender serves as a consultant for Atara Biotherapeutics.
Peter Csurhes: nothing to disclose.
Corey Smith serves as a consultant for Atara Biotherapeutics.
Nanette Douglas: nothing to disclose.
Michelle Neller: nothing to disclose.
Leone Beagley: nothing to disclose.
Sweera Rehan: nothing to disclose.
Tracey Hopkins: nothing to disclose.
Kate Thompson: nothing to disclose.
Stefan Blum serves as a Member of the Advisory Boards of Teva Pharmaceuticals and Roche.
Kerryn Green: nothing to disclose.
Zara Ioannides: nothing to disclose.
Alan Coulthard: nothing to disclose.
Kaye Hooper serves as a Member of the Advisory Boards of Merck Serono Australia and Biogen Australia.
Scott Burrows has received a licence fee payment from Atara Biotherapeutics.
Rajiv Khanna serves as a consultant and Member of the Scientific Advisory Board of Atara Biotherapeutics and has received a licence fee payment and research funding from Atara Biotherapeutics; he is the Editor-in-Chief of Clinical & Translational Immunology.

Abstract: P785

Type: Poster

Abstract Category: Therapy - disease modifying - 31 Treatment of progressive MS

Background: Increasing evidence indicates a role for Epstein-Barr virus (EBV) infection in the pathogenesis of multiple sclerosis (MS). EBV-infected autoreactive B cells might accumulate in the central nervous system because of defective cytotoxic CD8+ T cell immunity.
Objective: To determine the safety of treating progressive MS patients with autologous EBV-specific T-cells.
Methods: This 26 week phase I trial is designed to treat 5 patients with secondary progressive MS (SPMS) and 5 patients with primary progressive MS (PPMS) with autologous EBV-specific T cells targeting EBV nuclear antigen-1, latent membrane protein 1 (LMP1) and LMP2A. Four escalating doses are administered biweekly.
Results: To date (May 2017), 8 patients (5 SPMS and 3 PPMS) have received the full course of therapy, including one SPMS patient who had been treated 4 years earlier (compassionate use) and was treated on study owing to worsening symptoms after 3.5 years of sustained improvement. Five of these patients have experienced clinical improvements. Exploratory analyses suggest that clinical improvement correlates with the levels of EBV-specific reactivity and polyfunctionality (IFNγ/TNFα/IL2/CD107a expression) of the administered CD8+ T cells. No significant adverse events have been observed. One treatment-related adverse event, transient grade 1 dysgeusia likely related to DMSO, was observed. Of the first six patients, three experienced symptomatic and objective clinical improvement, commencing 2-8 weeks after the first infusion. Marked improvement occurred in one SPMS patient, with resolution of fatigue, increased manual dexterity, increased walking distance and improvement in lower limb tone, power, reflexes, sensation and coordination. A second SPMS patient had reduced fatigue, increased productivity and improved balance. A third patient (PPMS) had improved colour vision, visual acuity and manual dexterity and reduced fatigue, lower limb spasms and urinary urgency. The seventh (PPMS) and eight (SPMS) patients were most recently assessed at 6 weeks following their first T cell infusion and reported reduced fatigue and improved cognition. The ninth patient (PPMS) has so far received one T cell infusion.
Conclusion: Our findings, to date, of safety and clinical improvement set the stage for further clinical trials with autologous and allogeneic EBV-targeted T cell therapy in MS. Updated data for all 10 patients will be presented at the meeting.
Disclosure:
Michael Pender serves as a consultant for Atara Biotherapeutics.
Peter Csurhes: nothing to disclose.
Corey Smith serves as a consultant for Atara Biotherapeutics.
Nanette Douglas: nothing to disclose.
Michelle Neller: nothing to disclose.
Leone Beagley: nothing to disclose.
Sweera Rehan: nothing to disclose.
Tracey Hopkins: nothing to disclose.
Kate Thompson: nothing to disclose.
Stefan Blum serves as a Member of the Advisory Boards of Teva Pharmaceuticals and Roche.
Kerryn Green: nothing to disclose.
Zara Ioannides: nothing to disclose.
Alan Coulthard: nothing to disclose.
Kaye Hooper serves as a Member of the Advisory Boards of Merck Serono Australia and Biogen Australia.
Scott Burrows has received a licence fee payment from Atara Biotherapeutics.
Rajiv Khanna serves as a consultant and Member of the Scientific Advisory Board of Atara Biotherapeutics and has received a licence fee payment and research funding from Atara Biotherapeutics; he is the Editor-in-Chief of Clinical & Translational Immunology.

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