Phase I Study of PHE885, a Fully Human BCMA-Directed CAR-T Cell Therapy for Relapsed/Refractory Multiple Myeloma Manufactured in &lt;2 Days Using the T-Charge TM Platform
Authors: Sperling Adam S. , Nikiforow Sarah , Nadeem Omar , Mo Clifton C , Laubach Jacob P. , Anderson Kenneth C. , Alonso Alejandro , Ikegawa Shuntaro , Prabhala Rao , Hernandez Rodriguez Diego , Daley Heather , Shaw Kit L. , Arihara Yohei , Ansari Soudeh , Quinn David S , Pearson David , Hack Anniesha , Treanor Louise M , Bu Dexiu , Mataraza Jennifer , Rispoli Lawrence , Credi Marc , Ritz Jerome , De Vita Serena , Munshi Nikhil C. 
Published: November 2021

Abstract
Background: Chimeric antigen receptor (CAR)-T cells are highly effective in patients (pts) with multiple myeloma (MM), but duration of response can be limited, and pts with rapidly progressing disease require a fast and reliable CAR-T cell manufacturing process. Here, we report initial clinical data from a Phase I trial assessing PHE885 manufactured using the T-Charge TM process and characterization of in vivo expansion, suggesting a preserved T-cell stemness (T scm) phenotype in pts with relapsed/refractory (r/r) MM (NCT04318327).
Methods: PHE885 is a unique and fully human BCMA CAR-T cell product manufactured using the novel T-Charge TM platform, which reduces ex vivo culture time to about 24 hours and takes &lt;2 days to manufacture the final product, thereby relying entirely on in vivo expansion after CAR-T cell infusion. Pts with MM r/r to ≥2 prior lines of treatment (tx), including an immunomodulatory drug, proteasome inhibitor, and an anti-CD38 monoclonal antibody, were eligible. Pts received fludarabine and cyclophosphamide for lymphodepletion prior to a single PHE885 intravenous injection. Primary objectives were safety, including dose-limiting toxicities (DLTs) and adverse events (AEs). Secondary objectives were clinical responses, evaluation of the T-Charge TM process, and pharmacokinetic properties.
Results: As of data cut (April 1, 2021), 7 pts were enrolled in the dose escalation portion; 1 pt failed screening (prolonged QTc), and 6 pts were successfully infused with PHE885. All pts were heavily pretreated, penta-refractory, and refractory to the last line of tx. Fixed doses received were 5×10 6 (n=5) and 14.3×10 6 CAR+ T cells (n=1). All 6 pts were eligible for safety and efficacy. Two DLTs were reported: asymptomatic grade 3 transaminitis in the pt infused with 14.3×10 6 CAR+ T cells, and asymptomatic grade 4 lipase increased in 1 pt infused with 5×10 6 CAR+ T cells. Treatment-related grade ≥3 AEs included anemia and neutropenia in all pts; thrombocytopenia (n=4, 67%); and leukopenia, cytokine release syndrome (CRS), ALT and AST increase, and decreased blood fibrinogen (each n=2, 33%). All pts experienced grade ≤3 CRS per Lee 2014 criteria; median times to CRS onset and resolution were 7 d (range, 4-9 d) and 22 d (range, 10-27 d), respectively. All pts received at least 1 dose each of steroids and tocilizumab; 3 pts received anakinra to manage CRS. Two pts experienced grade 2 neurotoxicity related to PHE885. Both events were nonserious and temporally associated with grade 3 CRS. No deaths occurred on study. At 1 mo after tx, all pts had achieved at least a partial response (PR), with complete response (CR) in 1 pt (17%) and very good PR in 2 pts (33%). Of 4 pts evaluable at 3 mo after tx, 2 had stringent CR, 1 had PR, and 1 pt in PR experienced progressive disease, presumed to be due to loss of BCMA. Of 3 pts evaluable for minimal residual disease (MRD) at 1 mo after tx, all were MRD negative: 2 at sensitivity of 10 -6 and 1 at 10 -5.
Robust cellular expansion was observed in all pts via qPCR and flow cytometry; maximum expansion (geometric mean C max) was 283000 copies/μg by qPCR and 69.3% of circulating T cells by flow cytometry. Maximum expansion was reached by 30 d, with median T max of 21.1 d by qPCR (16.4 d by flow cytometry). PHE885 was detectable in peripheral blood up to the latest measured sample for each pt (6 mo for the longest followed pt; range of follow-up, 1-6 mo). A naïve-like T-cell phenotype (T naïve+T scm) was preserved during manufacturing of all PHE885 products.
Conclusions: Initial data from this Phase I study demonstrate that low doses of BCMA CAR-T cells manufactured by T-Charge TM in &lt;2 days have encouraging clinical activity and a manageable safety profile in pts with r/r MM. PHE885 CAR-T cells expand rapidly in vivo, persist at relatively high levels for prolonged periods, and demonstrate a relatively immature T-cell phenotype. The trial is ongoing and updated data will be presented at the annual meeting.
Clinical trial information: NCT04318327
Figure 1 Figure 1.

Disclosures
Sperling: Adaptive: Consultancy. Nikiforow: Kite/Gilead: Other: ad HOC Advisory Boards; Novartis: Other: ad Hoc Advisory Boards; Iovance: Other: ad Hoc Advisory Boards; Glaxo Smith Kline (GSK): Other: ad Hoc Advisory Boards. Nadeem: Bristol Myer Squibb: Consultancy; GSK: Consultancy; Adaptive: Consultancy; Karyopharm: Consultancy; Takeda: Consultancy. Mo: Eli Lilly: Consultancy; Epizyme: Consultancy; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; AbbVIE: Consultancy. Anderson: Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Millenium-Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Scientific Founder of Oncopep and C4 Therapeutics: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Mana Therapeutics: Membership on an entity's Board of Directors or advisory committees. Ikegawa: Bristol Myers Squibb: Honoraria. Shaw: Orchard Therapeutics, Ltd: Current equity holder in publicly-traded company. Ansari: Novartis: Current Employment. Quinn: Novartis: Current Employment, Current equity holder in publicly-traded company. Pearson: Novartis: Current Employment, Current equity holder in publicly-traded company. Hack: Novartis: Current Employment. Treanor: Novartis: Current Employment, Current holder of individual stocks in a privately-held company, Divested equity in a private or publicly-traded company in the past 24 months, Patents & Royalties: no royalties as company-held patents. Bu: Novartis: Current Employment, Patents & Royalties: Co-inventor on patent applications. Mataraza: Novartis: Current Employment, Current holder of stock options in a privately-held company. Rispoli: Novartis: Current Employment. Credi: Novartis: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Ritz: Amgen: Research Funding; Equillium: Research Funding; Kite/Gilead: Research Funding; Avrobio: Membership on an entity's Board of Directors or advisory committees; Akron: Consultancy; Biotech: Consultancy; Blackstone Life Sciences Advisor: Consultancy; Clade Therapeutics, Garuda Therapeutics: Consultancy; Immunitas Therapeutic: Consultancy; LifeVault Bio: Consultancy; Novartis: Consultancy; Rheos Medicines: Consultancy; Talaris Therapeutics: Consultancy; TScan Therapeutics: Consultancy. De Vita: Novartis: Current Employment. Munshi: Celgene: Consultancy; Amgen: Consultancy; Takeda: Consultancy; Adaptive Biotechnology: Consultancy; Abbvie: Consultancy; Oncopep: Consultancy, Current equity holder in publicly-traded company, Other: scientific founder, Patents & Royalties; Janssen: Consultancy; Karyopharm: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Legend: Consultancy; Bristol-Myers Squibb: Consultancy.