Nicotinamide enhances natural killer cell function and yields remissions in patients with non-Hodgkin lymphoma

Frank Cichocki; Bin Zhang; Cheng Ying Wu; Emily Chiu; Abderrahman Day; Roddy S. O’Connor; Dima Yackoubov; Ronit Simantov; David H. McKenna; Qing Cao; Todd E. Defor; Murali Janakiram; Rose Wangen; Zuzan Cayci; Nathaniel Snyder; Akhilesh Kumar; Bartosz Grzywacz; Justin Hwang; Yona Geffen; Jeffrey S. Miller; Joseph Maakaron; Veronika Bachanova

doi:10.1126/scitranslmed.ade3341

Nicotinamide enhances natural killer cell function and yields remissions in patients with non-Hodgkin lymphoma

Frank Cichocki, Bin Zhang, Cheng Ying Wu, Emily Chiu, Abderrahman Day, Roddy S. O’Connor, Dima Yackoubov, Ronit Simantov, David H. McKenna, Qing Cao, Todd E. Defor, Murali Janakiram, Rose Wangen, Zuzan Cayci, Nathaniel Snyder, Akhilesh Kumar, Bartosz Grzywacz, Justin Hwang, Yona Geffen, Jeffrey S. MillerJoseph Maakaron, Veronika Bachanova

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7 Scopus citations

Abstract

Allogeneic natural killer (NK) cell adoptive transfer has shown the potential to induce remissions in relapsed or refractory leukemias and lymphomas, but strategies to enhance NK cell survival and function are needed to improve clinical efficacy. Here, we demonstrated that NK cells cultured ex vivo with interleukin-15 (IL-15) and nicotinamide (NAM) exhibited stable induction of L-selectin (CD62L), a lymphocyte adhesion molecule important for lymph node homing. High frequencies of CD62L were associated with elevated transcription factor forkhead box O1 (FOXO1), and NAM promoted the stability of FOXO1 by preventing proteasomal degradation. NK cells cultured with NAM exhibited metabolic changes associated with elevated glucose flux and protection against oxidative stress. NK cells incubated with NAM also displayed enhanced cytotoxicity and inflammatory cytokine production and preferentially persisted in xenogeneic adoptive transfer experiments. We also conducted a first-in-human phase 1 clinical trial testing adoptive transfer of NK cells expanded ex vivo with IL-15 and NAM (GDA-201) combined with monoclonal antibodies in patients with relapsed or refractory non-Hodgkin lymphoma (NHL) and multiple myeloma (MM) (NCT03019666). Cellular therapy with GDA-201 and rituximab was well tolerated and yielded an overall response rate of 74% in 19 patients with advanced NHL. Thirteen patients had a complete response, and 1 patient had a partial response. GDA-201 cells were detected for up to 14 days in blood, bone marrow, and tumor tissues and maintained a favorable metabolic profile. The safety and efficacy of GDA-201 in this study support further development as a cancer therapy.

Original language	English (US)
Article number	eade3341
Journal	Science Translational Medicine
Volume	15
Issue number	705
DOIs	https://doi.org/10.1126/scitranslmed.ade3341
State	Published - 2023

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Publisher Copyright:
Copyright © 2023 The Authors, some rights reserved.

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Cichocki, F., Zhang, B., Wu, C. Y., Chiu, E., Day, A., O’Connor, R. S., Yackoubov, D., Simantov, R., McKenna, D. H., Cao, Q., Defor, T. E., Janakiram, M., Wangen, R., Cayci, Z., Snyder, N., Kumar, A., Grzywacz, B., Hwang, J., Geffen, Y., ... Bachanova, V. (2023). Nicotinamide enhances natural killer cell function and yields remissions in patients with non-Hodgkin lymphoma. Science Translational Medicine, 15(705), Article eade3341. https://doi.org/10.1126/scitranslmed.ade3341

Cichocki, F , Zhang, B, Wu, CY, Chiu, E, Day, A, O’Connor, RS, Yackoubov, D, Simantov, R, McKenna, DH , Cao, Q , Defor, TE, Janakiram, M, Wangen, R, Cayci, Z, Snyder, N, Kumar, A, Grzywacz, B, Hwang, J, Geffen, Y, Miller, JS , Maakaron, J & Bachanova, V 2023, 'Nicotinamide enhances natural killer cell function and yields remissions in patients with non-Hodgkin lymphoma', Science Translational Medicine, vol. 15, no. 705, eade3341. https://doi.org/10.1126/scitranslmed.ade3341

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abstract = "Allogeneic natural killer (NK) cell adoptive transfer has shown the potential to induce remissions in relapsed or refractory leukemias and lymphomas, but strategies to enhance NK cell survival and function are needed to improve clinical efficacy. Here, we demonstrated that NK cells cultured ex vivo with interleukin-15 (IL-15) and nicotinamide (NAM) exhibited stable induction of L-selectin (CD62L), a lymphocyte adhesion molecule important for lymph node homing. High frequencies of CD62L were associated with elevated transcription factor forkhead box O1 (FOXO1), and NAM promoted the stability of FOXO1 by preventing proteasomal degradation. NK cells cultured with NAM exhibited metabolic changes associated with elevated glucose flux and protection against oxidative stress. NK cells incubated with NAM also displayed enhanced cytotoxicity and inflammatory cytokine production and preferentially persisted in xenogeneic adoptive transfer experiments. We also conducted a first-in-human phase 1 clinical trial testing adoptive transfer of NK cells expanded ex vivo with IL-15 and NAM (GDA-201) combined with monoclonal antibodies in patients with relapsed or refractory non-Hodgkin lymphoma (NHL) and multiple myeloma (MM) (NCT03019666). Cellular therapy with GDA-201 and rituximab was well tolerated and yielded an overall response rate of 74% in 19 patients with advanced NHL. Thirteen patients had a complete response, and 1 patient had a partial response. GDA-201 cells were detected for up to 14 days in blood, bone marrow, and tumor tissues and maintained a favorable metabolic profile. The safety and efficacy of GDA-201 in this study support further development as a cancer therapy.",

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AU - Day, Abderrahman

AU - O’Connor, Roddy S.

AU - Yackoubov, Dima

AU - Simantov, Ronit

AU - McKenna, David H.

AU - Cao, Qing

AU - Defor, Todd E.

AU - Janakiram, Murali

AU - Wangen, Rose

AU - Cayci, Zuzan

AU - Snyder, Nathaniel

AU - Kumar, Akhilesh

AU - Grzywacz, Bartosz

AU - Hwang, Justin

AU - Geffen, Yona

AU - Miller, Jeffrey S.

AU - Maakaron, Joseph

AU - Bachanova, Veronika

PY - 2023

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AB - Allogeneic natural killer (NK) cell adoptive transfer has shown the potential to induce remissions in relapsed or refractory leukemias and lymphomas, but strategies to enhance NK cell survival and function are needed to improve clinical efficacy. Here, we demonstrated that NK cells cultured ex vivo with interleukin-15 (IL-15) and nicotinamide (NAM) exhibited stable induction of L-selectin (CD62L), a lymphocyte adhesion molecule important for lymph node homing. High frequencies of CD62L were associated with elevated transcription factor forkhead box O1 (FOXO1), and NAM promoted the stability of FOXO1 by preventing proteasomal degradation. NK cells cultured with NAM exhibited metabolic changes associated with elevated glucose flux and protection against oxidative stress. NK cells incubated with NAM also displayed enhanced cytotoxicity and inflammatory cytokine production and preferentially persisted in xenogeneic adoptive transfer experiments. We also conducted a first-in-human phase 1 clinical trial testing adoptive transfer of NK cells expanded ex vivo with IL-15 and NAM (GDA-201) combined with monoclonal antibodies in patients with relapsed or refractory non-Hodgkin lymphoma (NHL) and multiple myeloma (MM) (NCT03019666). Cellular therapy with GDA-201 and rituximab was well tolerated and yielded an overall response rate of 74% in 19 patients with advanced NHL. Thirteen patients had a complete response, and 1 patient had a partial response. GDA-201 cells were detected for up to 14 days in blood, bone marrow, and tumor tissues and maintained a favorable metabolic profile. The safety and efficacy of GDA-201 in this study support further development as a cancer therapy.

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Nicotinamide enhances natural killer cell function and yields remissions in patients with non-Hodgkin lymphoma

Abstract

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