On December 6, 2020 Fate Therapeutics, Inc. (NASDAQ: FATE), a clinical-stage biopharmaceutical company dedicated to the development of programmed cellular immunotherapies for cancer and immune disorders, reported a patient case study from the Company’s Phase 1 clinical trial of FT596, its universal, off-the-shelf, CD19-targeted chimeric antigen receptor (CAR) natural killer (NK) cell product candidate, at the 62nd Annual Society of Hematology Annual Meeting and Exposition (Press release, Fate Therapeutics, DEC 6, 2020, View Source [SID1234572226]).

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The case study described a heavily pre-treated patient with diffuse large B-cell lymphoma (DLBCL) who achieved a partial response following administration of a single-dose treatment cycle of FT596 as a monotherapy in the first dose cohort of 30 million cells. The patient subsequently received a second single-dose treatment cycle of FT596, which resulted in a deepening response as evidenced by further decrease in both tumor size and metabolic activity. No dose-limiting toxicities, no FT596-related serious adverse events, and no events of any grade of cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, or graft-versus-host disease were reported by the investigator. The patient had previously received seven prior treatment regimens, including five rituximab-containing regimens as well as autologous stem cell transplantation, and was most recently refractory to an experimental cellular therapy.

"The safety, pharmacokinetics and clinical activity observed following both the first and second single-dose treatment cycles of FT596 are compelling, especially when considering that the administered cell dose was significantly lower than the recommended cell dose of FDA-approved autologous CD19-targeted CAR T-cell therapies and that the heavily pre-treated patient was refractory to last prior therapy," said Dr. Wayne Chu, Senior Vice President, Clinical Development of Fate Therapeutics. "We are excited the CAR component of FT596 has shown clinical activity at this low dose level, and we continue to enroll patients in dose escalation with FT596 as a monotherapy and in combination with rituximab. Our recent Phase 1 clinical data with FT516 in combination with rituximab, which demonstrate the potential of our novel hnCD16 Fc receptor to potentiate ADCC and drive complete responses, support our belief that the multi-antigen targeting functionality of FT596 may offer best-in-class potential for patients with B-cell malignancies."

FT596 is derived from a clonal master induced pluripotent stem cell (iPSC) line engineered with three anti-tumor modalities: a proprietary CAR optimized for NK cell biology that targets CD19; a novel high-affinity, non-cleavable CD16 (hnCD16) Fc receptor that enhances antibody-dependent cellular cytotoxicity (ADCC), a potent anti-tumor mechanism by which NK cells recognize, bind and kill antibody-coated cancer cells; and an IL-15 receptor fusion that augments NK cell activity. The open-label, multi-center Phase 1 clinical trial is designed to assess the safety and activity of a single-dose treatment cycle of FT596 in up to four dose cohorts (30 million cells; 90 million cells; 300 million cells and 900 million cells) as a monotherapy and in combination with CD20-targeted monoclonal antibody therapy for the treatment of relapsed / refractory B-cell malignancies. Under the clinical protocol, the Company may seek consent of the U.S. Food and Drug Administration (FDA) for administration of a second single-dose treatment cycle.

Patient History
The patient, a 76 year old woman with refractory DLBCL, had received seven prior lines of therapy, which included five rituximab-containing regimens, autologous stem cell transplantation, and two experimental cellular therapies. Of note, the patient was most recently refractory to an experimental NK cell therapy regimen comprised of fludarabine and cyclophosphamide lympho-conditioning followed by ex vivo expanded, donor-derived NK cells (≥1 billion cells), IL-2, and rituximab. Approximately 3.5 months from last prior therapy, the patient enrolled into the first dose cohort of FT596 as a monotherapy at 30 million cells.

Safety
The patient underwent fludarabine and cyclophosphamide lympho-conditioning and was administered a single dose of FT596 as a monotherapy at 30 million cells (Study Day 1). Following FDA consent for continued treatment based on review of the clinical data from the first FT596 treatment cycle, the patient underwent another round of lympho-conditioning and was administered a second dose of FT596 as a monotherapy at 30 million cells (Study Day 47). No dose-limiting toxicities, and no cases of any grade of cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, or graft-versus-host disease, were observed. No FT596-related serious adverse events (SAEs) were reported, and the only Grade ≥3 adverse events deemed possibly related to FT596 were neutrophil count decreased, white blood cell count decreased, and lymphocyte count decreased. All other Grade ≥3 adverse events were consistent with lympho-conditioning chemotherapy and prior treatment regimens. No evidence of anti-product T- or B-cell mediated host-versus-product alloreactivity was detected.

Clinical Response & Pharmacokinetics
The patient achieved a partial response as of the Day 29 protocol-defined response assessment (Study Day 29), with a greater than 50% reduction in tumor size and a substantial reduction in metabolic activity as assessed by PET-CT scan per Lugano 2014 criteria. The protocol-defined response assessment following the second FT596 treatment cycle (Study Day 75) showed a deepening response, with an additional 33% reduction in tumor size and further reduction in metabolic activity. The duration of response, which was not aided by further therapeutic intervention, was 3.8 months and is comparable to that of FDA-approved autologous CD19 CAR-T cell therapy among patients who achieve partial response as best overall response (2.1-3.4 months; Yescarta USPI; Kymriah USPI). The pharmacokinetic profile of both FT596 treatment cycles was consistent and indicative of cell expansion, with peak peripheral blood exposure observed on the eighth day following administration of FT596 (1732 and 1150 vector transgene copies per µg of genomic DNA, respectively), which further validates that retreatment with FT596 conferred additional clinical benefit.

Dose escalation in the FT596 Phase 1 study is currently ongoing in the second dose cohort of 90 million cells as monotherapy and in combination with CD20-targeted monoclonal antibody therapy for patients with relapsed / refractory B-cell lymphoma. In addition, for patients with relapsed / refractory chronic lymphocytic leukemia, the Company has initiated enrollment in the first dose cohort of 30 million cells as monotherapy and plans to begin enrollment in combination with obinutuzumab upon dose-limiting toxicity clearance of monotherapy in the first dose cohort.

FT596 is also currently being evaluated in an investigator-initiated Phase 1 clinical trial sponsored by investigators from the Masonic Cancer Center, University of Minnesota for patients with B-cell lymphoma who have undergone autologous hematopoietic stem cell transplant and are considered high risk for early relapse (NCT04555811). Up to three dose cohorts of FT596, beginning at 90 million cells per dose, in combination with CD20-targeted monoclonal antibody will be assessed.

About Fate Therapeutics’ iPSC Product Platform
The Company’s proprietary induced pluripotent stem cell (iPSC) product platform enables mass production of off-the-shelf, engineered, homogeneous cell products that can be administered with multiple doses to deliver more effective pharmacologic activity, including in combination with other cancer treatments. Human iPSCs possess the unique dual properties of unlimited self-renewal and differentiation potential into all cell types of the body. The Company’s first-of-kind approach involves engineering human iPSCs in a one-time genetic modification event and selecting a single engineered iPSC for maintenance as a clonal master iPSC line. Analogous to master cell lines used to manufacture biopharmaceutical drug products such as monoclonal antibodies, clonal master iPSC lines are a renewable source for manufacturing cell therapy products which are well-defined and uniform in composition, can be mass produced at significant scale in a cost-effective manner, and can be delivered off-the-shelf for patient treatment. As a result, the Company’s platform is uniquely capable of overcoming numerous limitations associated with the production of cell therapies using patient- or donor-sourced cells, which is logistically complex and expensive and is subject to batch-to-batch and cell-to-cell variability that can affect clinical safety and efficacy. Fate Therapeutics’ iPSC product platform is supported by an intellectual property portfolio of over 300 issued patents and 150 pending patent applications.

About FT596
FT596 is an investigational, universal, off-the-shelf natural killer (NK) cell cancer immunotherapy derived from a clonal master induced pluripotent stem cell (iPSC) line engineered with three anti-tumor functional modalities: a proprietary chimeric antigen receptor (CAR) optimized for NK cell biology that targets B-cell antigen CD19; a novel high-affinity 158V, non-cleavable CD16 (hnCD16) Fc receptor, which has been modified to prevent its down-regulation and to enhance its binding to tumor-targeting antibodies; and an IL-15 receptor fusion (IL-15RF) that augments NK cell activity. In preclinical studies of FT596, the Company has demonstrated that dual activation of the CAR19 and hnCD16 targeting receptors enhances cytotoxic activity, indicating that multi-antigen engagement may elicit a deeper and more durable response. Additionally, in a humanized mouse model of lymphoma, FT596 in combination with the anti-CD20 monoclonal antibody rituximab showed enhanced killing of tumor cells in vivo as compared to rituximab alone. FT596 is being investigated in an open-label, multi-center Phase 1 clinical trial for the treatment of relapsed / refractory B-cell lymphoma as a monotherapy and in combination with rituximab, and for the treatment of relapsed / refractory chronic lymphocytic leukemia (CLL) as a monotherapy and in combination with obinutuzumab (NCT04245722).