Melissa Ann Geller, MD @UMNews #ASCO20 #ovariancancer APOLLO: A phase I study of adaptive memory natural killer (NK) cells in recurrent ovarian cancer

Melissa Ann Geller, MD @UMNews #ASCO20 #ovariancancer APOLLO: A phase I study of adaptive memory natural killer (NK) cells in recurrent ovarian cancer

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Description:
Melissa Ann Geller, MD of the University of Minnesota speaks about the ASCO 2020 abstract APOLLO: A phase I study of adaptive memory natural killer (NK) cells in recurrent ovarian cancer.


Background:
A subset of long-lived CD57+NKG2C+ adaptive NK cells with increased antibody-dependent cellular cytotoxicity and resistance to tumor-suppressive mechanisms is caused by human cytomegalovirus ( CMV) infection. To manufacture modulated adaptive NK cells (FATE-NK100) from CMV+ haploidentical donors for adoptive transfer, we developed a 7-day culture method using a GSK3 inhibitor and IL-15. Phase I Apollo trial measures the maximum tolerated / maximum feasible dose (MTD / MFD) of FATE-NK100 administered intraperitoneally (IP) to treat recurrent ovarian, fallopian tube, and primary peritoneal cancer that is platinum-sensitive or -resistant.

Approaches:
Three dose cohorts ([DC]; 1 ⁇ 107 cells / kg; > 1 ⁇ 107 cells / kg to ⁇ 3 ⁇ 107 cells / kg; or > 3 ⁇ 107 to ⁇ 10 ⁇ 107 cells / kg) were used to test FATE-NK100 via IP port after fludarabine 25 mg / m2 IV and cyclophosphamide 300 mg / m2 IV lympho-conditioning on days −6 and −5. After infusion with FATE-NK100 on day 0, IP was given to rhIL-2 at 6 million IU 3 times a week for 6 doses for activation of NK in vivo. Up until response assessment (day 28), IP fluid and peripheral blood were collected daily. Patients with or better of stable illness were eligible for retreat. Tumor biopsies were obtained pre- and post-treatment.

Outcomes:
To date, nine patients have been treated without any dose-limiting toxicity (DLTs). Clinical benefit-based retreat was conducted in 3 patients (33 percent), 2 in stable disease (DC 2) and 1 in partial remission (48 percent reduction of tumor, DC 3). For PK and functional analysis IP samples were collected. In 5 of 6 patients with evaluable samples, the FATE-NK100 product was detected by flow cytometry (range 4.8 percent-91.2 percent donor NK cells at day +5-7). In 1 patient, where FATE-NK100 persisted to day +21, retreat samples were available showing that repeated IP dosing did not accelerate the clearance of donor NK cells. Measurement of NK cell CD107a degranulation or IFNg production in response to K562 targets in the same patient showed sustained improved in vivo activity of FATE-NK100 compared to endogenous NK cells in patient (e.g. at Day +12 CD107a+ NK was 39.0 percent vs. 22.5 percent cycle 1 and 40.3 percent vs. 18.2 percent retreat cycle 2 and IFNg+ NK was 12.3 percent vs. 5.9 percent cycle 2)


Conclusions:
IP delivery of FATE-NK100 is healthy and has a clinical advantage in 3/9 treated patients. The allogeneic product cells survive and have enhanced activity for up to 21 days, even after the retreat, relative to patient NK cells. This phase I study of recurrent/refractory ovarian cancer demonstrates potential for the delivery of IP NK cells. Data on clinical trials: NCT006528999.
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