Off-The-Shelf CAR T Cells Show Early Promise B-Cell Malignancies

The off-the-shelf iPSC-derived NK Cell agents, FT516 AND FT596, which are being developed for the treatment of B-cell malignancies, show promise and early clinical benefit, according to recent data released during a press conference by Fate Therapeutics. 

“Our proprietary HNC16FC receptor has been specifically modified to maximize ADCD by preventingCD16 downregulation and by binding more effectively to tumor targeting antibodies for enhanced anti-tumor activity,” said Scott Wolchko, president and CEO of Fate Therapeutics.

While similar products, they have different treatment regimens. Patients can receive up to 2 cycles of FT516, totaling up to 6 doses. Each cycle contains 3 doses, given on days 1, 8, and 15. Patients can receive only 1 dose of 5T596. Patients can receive an additional dose only after receiving permission by the FDA.

For the phase 1 FT516 study, which included 13 patients at the time of analysis, the median age of patients was 65 (range, 28-75). The median number of prior therapies was 3 and the median prior of CD19-targeted CAR T-cell therapy was 5. An aggressive histology was seen in 77% of patients and 46% had refractory disease. Sixty-two percent of patients had elevated lactate dehydrogenase (LDH).

For patients who received 3 doses of 90 million (M) cells of the agent plus IL-2, the overall response (OR) was 75% and the complete response (CR) was 50%. For patients who received 3 doses of 300M cells of the agent plus IL-2, the OR is 71% and the CR is 57%.

When given in combination with rituximab for the treatment of B-cell lymphoma, 55% of patients had a CR at 3 months. Additionally, 45% of patients had an ongoing response at 4.6 to 9.5 months.

“Overall, we remain highly encouraged by the data with FT516. The safety profile response rate and durability of response demonstrate that FT516 and B effectively combined with CD20 targeted monoclonal antibody to drive meaningful therapeutic benefit and difficult to treat patients, including those with aggressive lymphomas with refractory disease,” said Yu-Waye Chu, MD, senior vice president of clinical development of Fate Therapeutics. 

In terms of safety, no cases of graft versus host disease (GvHD), dose-limiting toxicities (DLT), or Immune effector cell-associated neurotoxicity syndrome (ICAN) were reported. All-grade infection was seen in 31% of patients across all dose levels.

One such patient, a 36-year-old male with primary refractory high-grade B-cell lymphoma, Burkitt-like, who had received 7 prior therapies and was refractory to all other prior therapies other than CAR T-cell therapy, achieved a CR with the combination. The patient remains in CR at 4.9 months.

Similar promise was seen FT596 as both a monotherapy and in combination with rituximab. For the monotherapy arm of the phase 1 study, the median age was 69 and the median number of prior therapies was 4.5 and the median number of prior CD19-targeted CAR T cell therapy was 3. Half had an aggressive histology and 40% had refractory disease. Elevated LDH levels were seen in 40% of patients. 

In the combination arm, the median age was 62.5. The median number of prior therapies was 4 and the median number of prior CD19-targeted CAR T-cell therapies was 4. Seventy percent had an aggressive histology and 60% had refractory disease. Half had elevated LDH levels.

At a dose of 30M, no patients had a CR in either arm. At a dose of 90M, 2 of 4 patients in the monotherapy arm had a CR and 2 of 4 patients in the combination had a CR. At a dose of 300M, 1 of 3 patients in the monotherapy arm and 2 of 3 patients in the combination arm had a CR.

In terms of safety, no cases of GvHD, DLT, or ICANS were reported. All-grade infection was seen in 40% of patients across all dose levels.

“Data for FT596. monotherapy suggests a highly favorable safety and tolerability profile differentiated from T cell-based modalities. The data also indicates that the safety and tolerability profile of FT596 is not adversely affected by the addition of rituximab with respect to adverse events of interest,” Chu said.

“Cell therapies hold extraordinary potential. The business of making and delivering a cell therapy is massively complex, very often personalized, and far too limited with respect to patient reach. Our vision is to develop and deliver cell therapies in a manner similar to monoclonal antibody therapy, or renewable cell line is used for manufacturer product is mass produced in a cost-effective manner,” said Sarah Cooley, MD, MS, the senior vice president of clinical translation at Fate Therapeutics. The product is conveniently administered in a thought infused manner, and many patients have access to and receive the product with the urgency needed to treat cancer.”

_References:

_{1.B-cell Lymphoma Franchise Update. Fate Theraputics. August 19, 2021}

_{2.Fate Therapeutics Announces Positive Interim Clinical Data from its FT596 and FT516 Off-the-shelf, iPSC-derived NK Cell Programs for B-cell Lymphoma. News release. Fate Therapeutics. August 19, 2021. Accessed August 20, 2021. https://bit.ly/3AW5npS.}