Autologous cellular therapy for myeloma: Giving ex vivo expanded NK cells their due
Authors: Roman M. Shapiro, Rizwan Romee
Journal: Cell Reports Medicine (2022)

Ex vivo feeder-free autologous NK cell expansion is an efficient modality for clinical translation. In this issue of Cell Reports Medicine, Nahi et al. describe the use of this approach as consolidation therapy for multiple myeloma,1Nahi H. Chrobok M. Meinke S. Gran C. Marquardt N. Afram G. Sutlu T. Gilljam M. Stellan B. Wagner A.K. et al.Autologous NK Cells as Consolidation Therapy Following Stem Cell Transplantation in Multiple Myeloma.Cell Reports Medicine. 2022; 3: 100508-1-100508-11Google Scholar thereby reviving an alternate avenue for NK cell therapy. Ex vivo feeder-free autologous NK cell expansion is an efficient modality for clinical translation. In this issue of Cell Reports Medicine, Nahi et al. describe the use of this approach as consolidation therapy for multiple myeloma,1Nahi H. Chrobok M. Meinke S. Gran C. Marquardt N. Afram G. Sutlu T. Gilljam M. Stellan B. Wagner A.K. et al.Autologous NK Cells as Consolidation Therapy Following Stem Cell Transplantation in Multiple Myeloma.Cell Reports Medicine. 2022; 3: 100508-1-100508-11Google Scholar thereby reviving an alternate avenue for NK cell therapy. Multiple myeloma remains an incurable disease. Autologous stem cell transplantation (ASCT) remains one of the mainstays of available intensive therapies for eligible patients, often followed by long-term maintenance therapy with either an immonomodulator or proteasome inhibitor.2Rajkumar S.V. Multiple myeloma: 2020 update on diagnosis, risk-stratification and management.Am. J. Hematol. 2020; 95: 548-567Crossref PubMed Scopus (395) Google Scholar However, with a median age of diagnosis of 65–70, intensive therapies that attain remission and maintain long-term control of disease may be challenging to administer.3Kaweme N.M. Changwe G.J. Zhou F. Approaches and Challenges in the Management of Multiple Myeloma in the Very Old: Future Treatment Prospects.Front. Med. (Lausanne). 2021; 8: 612696Crossref Scopus (10) Google Scholar Furthermore, the long-term use of maintenance therapy has a number of important side effects, including a higher risk of cytopenia, thrombotic events, secondary malignancy with lenalidomide, and neuropathy with proteasome inhibitors4Ho M. Zanwar S. Kapoor P. Gertz M. Lacy M. Dispenzieri A. Hayman S. Dingli D. Baudi F. Muchtar E. et al.The Effect of Duration of Lenalidomide Maintenance and Outcomes of Different Salvage Regimens in Patients with Multiple Myeloma (MM).Blood Cancer J. 2021; 11: 158Crossref Scopus (4) Google Scholar. The use of an alternative cellular therapy as consolidation following ASCT is an interesting and promising approach without these potential side effects. In this era of immunotherapy, NK cell therapies are coming into their own. With recent developments in the ability to purify, expand, and manipulate NK cells both ex vivo and in vivo, a new armamentarium of cellular therapy to complement T cell therapies is being developed for clinical application. Various methods have been developed for the generation and ex vivo expansion of NK cells for clinical use, including the use of feeder layers expressing membrane-bound IL-15 or IL-21 in addition to costimulatory molecules such as 4-1BB, as well as feeder-free approaches.5Lee D.A. Cellular therapy: Adoptive immunotherapy with expanded natural killer cells.Immunol. Rev. 2019; 290: 85-99Crossref PubMed Scopus (67) Google Scholar Nahi et al. demonstrate an adaptation of the latter approach, showing the feasibility of generating a clinical grade product for infusion in an efficient and cost-effective manner1Nahi H. Chrobok M. Meinke S. Gran C. Marquardt N. Afram G. Sutlu T. Gilljam M. Stellan B. Wagner A.K. et al.Autologous NK Cells as Consolidation Therapy Following Stem Cell Transplantation in Multiple Myeloma.Cell Reports Medicine. 2022; 3: 100508-1-100508-11Google Scholar. Such an approach, with the added advantage of using a closed system that reduces the risk of product contamination, is amenable to scale. While most NK cell therapies are allogeneic in origin, with their clinical efficacy in part dependent on HLA mismatch between donor and recipient,6Gill S. Olson J.A. Negrin R.S. Natural killer cells in allogeneic transplantation: effect on engraftment, graft- versus-tumor, and graft-versus-host responses.Biol. Blood Marrow Transplant. 2009; 15: 765-776Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar autologous NK cell therapy is nevertheless a viable consolidative strategy. Autologous products are easier to procure and do not suffer from some of the challenges of HLA mismatched cellular therapy; namely, failure to persist in an immune incompatible milieu and the off-target activation of the cellular product due to an abundance of targets in a non-immune compatible allogeneic recipient leading to exhaustion or anergy.7Judge S.J. Murphy W.J. Canter R.J. Characterizing the Dysfunctional NK Cell: Assessing the Clinical Relevance of Exhaustion, Anergy, and Senescence.Front. Cell. Infect. Microbiol. 2020; 10: 49Crossref PubMed Scopus (90) Google Scholar The latter excessive off-target activation that can result in NK cell exhaustion or anergy is prevented when the predominant target remains the tumor. Expansion and long-term persistence of adoptively transferred immunologically autologous NK cells has also been demonstrated in trials of cytokine-induced memory-like (CIML) NK cells collected from an allogeneic donor and infused into an immune compatible post-allogeneic stem cell transplant environment.8Foltz J.A. Berrien-Elliott M.M. Neal C. Foster M. McClain E. Schappe T. Desai S. Becker-Hapak M. Cashen A.F. Fehniger T.A. Cytokine-Induced Memory-like (ML) NK Cells Persist for > 2 Months Following Adoptive Transfer into Leukemia Patients with a MHC-Compatible Hematopoietic Cell Transplant (HCT).Blood. 2019; 134: 1954Crossref Google Scholar, 9Bednarski J.J. Zimmerman C. Berrien-Elliott M.M. Foltz J.A. Becker-Hapak M. Neal C.C. Foster M. Schappe T. McClain E. Pence P. et al.Donor Memory-like NK cells Persist and Induce Remissions in Pediatric Patients with Relapsed AML after Transplant.Blood. 2021; (blood.2021013972)https://doi.org/10.1182/blood.2021013972Crossref Scopus (25) Google Scholar, 10Gang M. Wong P. Berrien-Elliott M.M. Fehniger T.A. Memory-like natural killer cells for cancer immunotherapy.Semin. Hematol. 2020; 57: 185-193Crossref PubMed Scopus (30) Google Scholar Although technically derived from an allogeneic donor, these CIML NK cells were in fact autologous to the hematopoietic system of the recipient who previously received an allogeneic stem cell transplant from the same donor. The immune compatible environment facilitated the expansion and persistence of the post-transplant NK cell compartment. Furthermore, these cytokine-activated NK cells exhibited augmented activity against tumor targets and were associated with clinical responses when treating myeloid disease.8Foltz J.A. Berrien-Elliott M.M. Neal C. Foster M. McClain E. Schappe T. Desai S. Becker-Hapak M. Cashen A.F. Fehniger T.A. Cytokine-Induced Memory-like (ML) NK Cells Persist for > 2 Months Following Adoptive Transfer into Leukemia Patients with a MHC-Compatible Hematopoietic Cell Transplant (HCT).Blood. 2019; 134: 1954Crossref Google Scholar, 9Bednarski J.J. Zimmerman C. Berrien-Elliott M.M. Foltz J.A. Becker-Hapak M. Neal C.C. Foster M. Schappe T. McClain E. Pence P. et al.Donor Memory-like NK cells Persist and Induce Remissions in Pediatric Patients with Relapsed AML after Transplant.Blood. 2021; (blood.2021013972)https://doi.org/10.1182/blood.2021013972Crossref Scopus (25) Google Scholar, 10Gang M. Wong P. Berrien-Elliott M.M. Fehniger T.A. Memory-like natural killer cells for cancer immunotherapy.Semin. Hematol. 2020; 57: 185-193Crossref PubMed Scopus (30) Google Scholar As with other trials of autologous or immune compatible NK cell therapy, the adoptive transfer of ex vivo expanded NK cells is well-tolerated.1Nahi H. Chrobok M. Meinke S. Gran C. Marquardt N. Afram G. Sutlu T. Gilljam M. Stellan B. Wagner A.K. et al.Autologous NK Cells as Consolidation Therapy Following Stem Cell Transplantation in Multiple Myeloma.Cell Reports Medicine. 2022; 3: 100508-1-100508-11Google Scholar,9Bednarski J.J. Zimmerman C. Berrien-Elliott M.M. Foltz J.A. Becker-Hapak M. Neal C.C. Foster M. Schappe T. McClain E. Pence P. et al.Donor Memory-like NK cells Persist and Induce Remissions in Pediatric Patients with Relapsed AML after Transplant.Blood. 2021; (blood.2021013972)https://doi.org/10.1182/blood.2021013972Crossref Scopus (25) Google Scholar With a number of available platforms supporting the expansion and persistence of adoptively transferred NK cells, further enhancement of their cytotoxic potential with the use of chimeric antigens is a logical next step and an exciting way forward.10Gang M. Wong P. Berrien-Elliott M.M. Fehniger T.A. Memory-like natural killer cells for cancer immunotherapy.Semin. Hematol. 2020; 57: 185-193Crossref PubMed Scopus (30) Google Scholar As with leukemia and myelodysplastic syndrome where early phase NK cell therapy clinical trials have demonstrated feasibility and efficacy, multiple myeloma may represent the expansion of the myeloid frontier in which NK cell therapy is given its due. The authors declare no competing interests. Autologous NK cells as consolidation therapy following stem cell transplantation in multiple myelomaNahi et al.Cell Reports MedicineJanuary 28, 2022In BriefActivated and expanded autologous NK cells were repeatedly infused in patients with multiple myeloma following autologous HSCT. The study by Nahi et al. shows safety and demonstrates efficacy parameters. It opens up the possibility to use autologous NK cells in clinical settings, either alone or as parts of combination therapies. Full-Text PDF Open Access