Autologous stem cell transplant recipients tolerate haploidentical related‐donor natural killer cell–enriched infusions

Abstract

BACKGROUND: In the setting of allogeneic stem cell transplantation (SCT), infusing natural killer (NK) cells from a major histocompatibility complex (MHC)‐mismatched donor can mediate an antileukemic effect. The graft‐versus‐tumor effect after autologous stem cell transplantation (ASCT) may result in less disease relapse. STUDY DESIGN AND METHODS: We performed a Phase I clinical trial to assess the safety and feasibility of infusing distantly processed donor NK‐enriched mononuclear cell (NK‐MNC) infusions from a MHC haplotype–mismatched (haploidentical) donor to patients who recently underwent ASCT for a hematologic malignancy. On Day 1, peripheral blood MNCs were obtained by steady‐state leukapheresis and sent from Boston to the Production Assistance for Cellular Therapies (PACT) facility at the University of Minnesota, where immunomagnetic depletion of CD3 cells was performed on Day 2. NK‐MNC products were then returned to Boston on Day 2 for infusion on Day 3. Toxicity, cellular product characteristics, and logistic events were monitored. RESULTS: At a median of 90 days (range, 49‐191 days) after ASCT, 13 patients were treated with escalating doses of NK‐MNCs per kilogram from 105 to 2 × 107. Adverse effects included Grade 2 rigors and muscle aches, but no Grade 3 or 4 events and no graft‐versus‐host disease or marrow suppression. One air courier delay occurred. NK‐MNC products were viable with cytotoxic activity after transport. CONCLUSION: CD3‐depleted, MHC‐mismatched allogeneic NK‐MNC infusions can be safely and feasibly administered to patients after ASCT after distant processing and transport, justifying further development of this approach.

Haploidentical Natural Killer Cells Infused before Allogeneic Stem Cell Transplantation for Myeloid Malignancies: A Phase I Trial

“…We did not identify a maximum tolerated dose of NK cells up to the maximum feasible dose attainable by apheresis and CD3 depletion of the product. This resulted in approximately 3 × 10 7 TNC/kg containing approximately 3 × 10 6 CD56 + CD3neg cells/kg, consistent with other reported NK cell studies utilizing apheresis-derived products 15-18 . This approach was associated with 100% engraftment and a relatively low rate of ≥ grade 3 aGvHD (10%), similar to that observed with conventional hematopoietic transplants.…”

Harnessing the power of alloreactivity without triggering graft-versus-host disease: how non-engrafting alloreactive cellular therapy might change the landscape of acute myeloid leukemia treatment

“…NEACT has been attempted as a treatment for metastatic and refractory solid tumors [55,60,61,63,67], as well as for hematologic malignancies other than AML [58,[60][61][62][63][66][67][68][69] (often reported along with AML cases in the studies described in Table 2). Despite occasional partial responses, the clinical results are muted overall (Supplemental Fig.…”

Opportunities and limitations of natural killer cells as adoptive therapy for malignant disease

“…In another study 5 of 19 adults with advanced AML achieved a complete haematological response following haploidentical NK-DLI and conditioning with low-dose total body irradiation or a combination of fludarabine and cyclophosphamide (42). Haploidentical NK cells have also been used with some success in concert with autologous transplantation for multiple myeloma (81, 82) and non Hodgkins lymphoma (83). Generally, without prior conditioning, allogeneic NK cells are only transiently detectable.…”