Phase 1 clinical trial using mbIL21 ex vivo–expanded donor-derived NK cells after haploidentical transplantation

Ciurea, Stefan O.; Schafer, Jolie; Bassett, Roland L.; Denman, Cecele J.; Cao, Kai; Willis, Daniel; Rondón, Gabriela; Chen, Julianne; Soebbing, Doris; Kaur, Indreshpal; Gulbis, Alison; Ahmed, Sairah; Rezvani, Katayoun; Shpall, Elizabeth J.; Lee, Dean A.; Champlin, Richard E.

doi:10.1182/blood-2017-05-785659

Cited by 288 publications

(276 citation statements)

References 39 publications

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“…18 In this study, FC21-NK cells were given before and after stem cell transplant and resulted in decreased relapse rate as well as lower occurrence of post-transplant viral reactivation and graft- versus -host disease. Peripheral blood taken from treated patients on day 30 post-SCT (21 days after 2 NK cell infusions) was analyzed for NK and T cell content, phenotype and function.…”

Section: Resultsmentioning

confidence: 99%

“…NK cells have shown to be very effective in preventing relapse in residual disease setting, under low tumor burden. 18,42 In several trials testing efficacy of haploidentical NK cells in patients with advanced relapsed or refractory tumors, responses were observed only in a small subgroup of patients and were hampered by co-expansion of Tregs which were thought to be of patient origin. 43-46 Our results suggest that expansion of Tregs may arise in the tumor microenvironment upon PD-L1 expression, and can even occur by expansion from the very small amount of T cells transferred as part of an adoptive NK cell product.…”

Section: Discussionmentioning

confidence: 99%

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PD-L1 blockade enhances anti-tumor efficacy of NK cells

2018

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Anti-PD-1/anti-PD-L1 therapies have shown success in cancer treatment but responses are limited to ~ 15% of patients with lymphocyte infiltrated, PD-L1 positive tumors. Hence, strategies that increase PD-L1 expression and tumor infiltration should make more patients eligible for PD-1/PD-L1 blockade therapy, thus improving overall outcomes. PD-L1 expression on tumors is induced by IFNγ, a cytokine secreted by NK cells. Therefore, we tested if PM21-particle expanded NK cells (PM21-NK cells) induced expression of PD-L1 on tumors and if anti-PD-L1 treatment enhanced NK cell anti-tumor efficacy in an ovarian cancer model. Studies here showed that PM21-NK cells secrete high amounts of IFNγ and that adoptively transferred PM21-NK cells induce PD-L1 expression on SKOV-3 cells in vivo. The induction of PD-L1 expression on SKOV-3 cells coincided with the presence of regulatory T cells (Tregs) in the abdominal cavity and within tumors. In in vitro experiments, anti-PD-L1 treatment had no direct effect on cytotoxicity or cytokine secretion by predominantly PD-1 negative PM21-NK cells in response to PD-L1+ targets. However, significant improvement of NK cell anti-tumor efficacy was observed in vivo when combined with anti-PD-L1. PD-L1 blockade also resulted in increased in vivo NK cell persistence and retention of their cytotoxic phenotype. These results support the use of anti-PD-L1 in combination with NK cell therapy regardless of initial tumor PD-L1 status and indicate that NK cell therapy would likely augment the applicability of anti-PD-L1 treatment.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

PD-L1 blockade enhances anti-tumor efficacy of NK cells

2018

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“…We recently reported on a phase I clinical study in highrisk myeloid leukemia patients treated with haploidentical transplants and multiple donor-derived, ex vivo expanded NK cell infusions using feeder cells expressing mbIL-21 [13]. In this dose escalation study, three doses of NK cells infused on Day-2, + 7 and + 28 (up to Day + 90), up to 1 × 10 8 /kg were safely infused without reaching a maximum tolerated dose and with no induction of grade 3 or 4 acute GvHD or higher TRM.…”

Section: Post-transplantation Nk Cell Therapymentioning

confidence: 99%

“…This association is true for both allogeneic and autologous transplantation [14][15][16][17]. Although the NK cells are about the first cells that can be detected in the peripheral blood after transplantation, their phenotype and function are immature [13]. It takes at least 3-6 months until these cells gain KIR expression and become functionally active to induce optimal anti-leukemia responses.…”

mentioning

confidence: 99%

“…While Symons and colleagues showed that recipients of an inhibitory KIR-genemismatched graft had lower relapse rate and improved survival and that patients with KIR Bx donor for recipients with homozygous A haplotype had improved non-relapse mortality and survival [10], Hosokai et al reported that KIR Bx donors for recipients with A/A haplotype had higher incidence of acute GVHD with no impact on non-relapse mortality, relapse or survival [11]. Low NK cell numbers and function early after transplantation have been observed related to the PTCy administration [12,13], while higher numbers of NK cells have been associated with better transplant outcomes [8][9][10][11]. This association is true for both allogeneic and autologous transplantation [14][15][16][17].…”

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confidence: 99%

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NK cell therapy after hematopoietic stem cell transplantation: can we improve anti-tumor effect?

Elssen

Ciurea

2017

Int J Hematol

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After decades since the discovery of natural killer (NK) cells as potential effector cells fighting malignantly transformed and virally infected cells, little progress has been made in their clinical application. This yet unrealized therapeutic effect is presumably, at least in part, due to low numbers of functional NK cells that could be obtained from the peripheral blood relative to tumor burden. Our group hypothesized that a relatively small NK cell number to targeted malignant cells is the cause of a lack of clinical effect. We pursued obtaining large numbers of NK cells via ex vivo expansion using feeder cells that express membrane-bound IL-21. Early clinical studies demonstrate safety of administration of ex vivo expanded NK cells after transplantation using this method and suggest a therapeutic benefit in terms on decreasing relapse rate and possible control of viral infections post-transplant can be achieved. Successful application of NK cells after hematopoietic stem cell transplantation opens the possibility to effectively enhance the anti-tumor effect and decrease relapse rate post-transplant. Moreover, high doses of NK cells could prove more efficacious in enhancing anti-tumor effects, not only in hematological malignancies, with our without transplantation, but also in solid tumor oncology.

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