On December 9, 2019 Precision BioSciences, Inc. (Nasdaq: DTIL), a genome editing company dedicated to improving life through the application of its pioneering, proprietary ARCUS platform, reported updated interim clinical data from the ongoing Phase 1 trial of its lead investigational off-the-shelf (allogeneic) chimeric antigen receptor (CAR) T cell therapy candidate, PBCAR0191, which targets the well characterized cancer cell surface protein CD19 (Press release, Precision Biosciences, DEC 9, 2019, View Source [SID1234552126]). PBCAR0191 is being developed in collaboration with Servier, an international pharmaceutical company. Data will be presented by Bijal Shah, MD, Moffitt Cancer Center, at the 61st Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) in Orlando, Florida, during a poster session from 6:00-8:00 p.m. ET today (Poster #4107, Hall B).

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"We are very encouraged by the evidence of cell-mediated anti-tumor activity and objective tumor responses that we have observed in both NHL and B-ALL patients treated with PBCAR0191, in the context of a manageable adverse event profile," said Chris Heery, MD, Chief Medical Officer of Precision BioSciences. "These data give us incremental confidence in our unique approach to allogeneic CAR T cell therapy, and we look forward to the potential of this therapy positively impacting the lives of more patients as the trial continues. At these still low dose levels, and using only mild lymphodepletion, it is remarkable to see anti-tumor activity in the majority of patients treated with PBCAR0191, including a durable response that lasted six months in one patient, and two complete responses. We have also seen preliminary evidence of dose dependent CAR T cell expansion and persistence, supporting our belief that cell persistence and clinical response is likely to increase as we increase dose level."

"New treatment options are desperately needed for patients with advanced NHL and B-ALL who often undergo multiple cycles of therapy with limited clinical benefit," commented Bijal Shah, MD, Moffitt Cancer Center. "These first-in-human data for PBCAR0191 suggest a tolerable safety profile and encouraging early evidence of clinical activity. Further study is required to determine durability of response at the current dose levels, as well as to establish safety and activity at Dose Level 3."

Patient baseline characteristics and trial overview
A total of nine patients are reported in these initial Phase 1 trial results, including six with NHL (three treated at Dose Level 1 and three treated at Dose Level 2), and three with B-ALL (all treated at Dose Level 2). Key baseline characteristics were as follows:

Dose Level 1 (3×105 cells/kg) – three NHL patients (two with diffuse large B cell lymphoma, one with mantle cell lymphoma) with a mean age of 54 years (min-max 34-64 years). Patients had received a median of four prior lines of therapy, with two patients being refractory to their last treatment, and one having previously relapsed following treatment with Yescarta, an FDA-approved autologous CD19-targeted CAR T therapy.
Dose Level 2 (1×106 cells/kg) – three NHL patients (all with mantle cell lymphoma) with a mean age of 74 years (min-max 71-77 years) who had received a median of two prior lines of therapy, with one patient refractory to their last treatment and two who had relapsed. Three B-ALL patients were also treated at DL2, with a mean age of 56 years (min-max 48-72 years); these patients had received a median of four prior lines of therapy – all three patients were refractory to their last treatment, with two patients having poor prognostic indicators at trial entry.
Patients received a single infusion of PBCAR0191 on day 0, following three days of lymphodepletion using fludarabine 30mg/m2/day and cyclophosphamide 500mg/m2/day. The primary objective of this Phase 1 portion of the ongoing Phase 1/2a trial is to evaluate safety as measured by the occurrence of dose limiting toxicities (DLTs). Secondary objectives include assessment of objective tumor responses using standard criteria, and further evaluation of adverse events (AEs) and adverse events of special interest, including graft-versus-host disease (GvHD), cytokine release syndrome (CRS), and IEC-associated neurotoxicity syndrome (ICANS). Data are presented as of a November 4, 2019 cutoff date, with additional critical data collected through December 2, 2019, including occurrence of CRS, ICANS, GvHD and evaluation of objective responses.

Safety of PBCAR0191
No serious adverse events or evidence of GvHD was observed through December 2, 2019. Three of the nine patients (33%) treated with PBCAR0191 developed CRS, including two Grade 1 cases and one Grade 2 case. One of the nine patients (11%) developed Grade 2 neurotoxicity. All events of CRS and neurotoxicity resolved, and no deaths occurred on study. In addition, one patient experienced a Grade 3 AE that was deemed related to PBCAR0191 (pain at the site of their tumor mass for one day following infusion), and one patient experienced Grade 4 lymphopenia (seven days duration) deemed related to PBCAR0191.

Clinical activity of PBCAR0191
Of the nine patients treated with PBCAR0191, seven (78%) had objective evidence of tumor shrinkage at any timepoint. Results also provide preliminary evidence of dose-dependent CAR T cell expansion and persistence.

In the NHL cohort, four of six patients (66%) achieved an objective response by Lugano 2014 criteria at day 28+, including three partial responses (two patients treated at DL1 and one patient treated at DL2) and one complete response (patient treated at DL2). As of December 2, 2019, one patient (treated at DL2) remains in complete response. One patient (treated at DL1) achieved a partial response then progressed six months after treatment with PBCAR0191. This was the most durable response observed to date and was also notable given the patient had relapsed following treatment with Yescarta. The remaining two NHL patients, one treated at DL1 and one at DL2, achieved early responses (one CR, one PR respectively) at day 14; both patients had evidence of disease progression at day 28.

In the B-ALL cohort treated at DL2, one of three patients (33%) achieved a complete response by NCCN 2017 criteria at day 28+ (with undetectable B-ALL in the bone marrow by flow cytometry, described as minimal residual disease (MRD) negative), and continues to be followed on study. The remaining two patients did not respond at day 28 – these patients had poor prognostic indicators on entry into the trial, one with prior CNS involvement and 95% blast infiltration into the bone marrow, and one with 77% blast infiltration into the bone marrow and disease refractory to two previous lines of treatment.

CAR T cell expansion and persistence in the peripheral blood was assessed at DL1 and DL2 by flow cytometry and qPCR. Evidence of a dose-dependent increase in cell expansion was observed between subjects treated at DL1 and DL2, as was a dose-dependent increase in CAR T cell persistence. B-cell aplasia and serum cytokine analysis also anecdotally correspond to observed clinical responses and CAR T cell expansion.

This trial is ongoing and treatment of patients at DL3 (3×106 cells/kg) recently commenced. Updated results, including from patients treated at DL3, are expected to be presented at a medical meeting in the first quarter of 2020.

Investigator Update & Webcast Information
Precision will host a live webcast of an investigator update event during the ASH (Free ASH Whitepaper) Annual Meeting to discuss these data, beginning at 8:15 p.m. ET on Monday, December 9, 2019. To access the webcast, please visit the "Events & Presentations" page within the Investors & Media section of the Precision BioSciences website at View Source A replay of the webcast will be available on the Precision website for 30 days following the event.

Precision’s Off-The-Shelf CAR T Platform
Precision is advancing a pipeline of cell-phenotype optimized allogeneic CAR T therapies, leveraging fully scaled, proprietary manufacturing processes. The platform is designed to maximize the number of patients who can potentially benefit from CAR T therapy by improving access to care through a well-tolerated lymphodepletion regimen, high quality cell products derived from carefully selected healthy donors, and a consistent final cell product with attributes in line with those previously observed to result in optimal safety and activity profiles. Precision carefully selects high-quality T cells derived from healthy donors as starting material, then utilizes its unique ARCUS genome editing technology to modify the cells via a single-step engineering process. By inserting the CAR gene at the T cell receptor (TCR) locus, this process knocks in the CAR while knocking out the TCR in a single step, creating a consistent product that can be reliably and rapidly manufactured and is designed to prevent graft-versus-host disease. Precision optimizes its CAR T therapy candidates for immune cell expansion in the body by maintaining a high proportion of naïve and central memory CAR T cells throughout the manufacturing process and in the final product.