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Maybe Space is Not the Final Frontier: Transplant and Cellular Therapies Boldly Go Where None Have Gone Before

December 12, 2023
Brittany Knick Ragon, MD, (@BKRagonMD)
Atrium Health Levine Cancer Institute, Charlotte, NC 

When considering how best to summarize the tremendous accomplishments in transplantation and cellular therapy (TCT) woven throughout the ASH program this year, I asked myself whether we have reached an asymptote of success in TCT. The continued treatment challenges and more optimistically described therapeutic opportunities seem infinite. Is there an end to the scientific novelty of TCT? As it turns out, perhaps space really is not the final frontier after all. TCT is and has always been a field of innovative exploration and endless potential, with TCT clinicians and scientists traversing the scientific frontier in a relentless pursuit of improved outcomes. It should come as no surprise that this year’s TCT presentations boldly go where none have gone before.  

As a transplanter, and fellow frontier explorer, I must disclose that few things bring me more joy at ASH than seeing TCT take center stage in the Plenary Scientific Session or the Late-Breaking Abstracts Session. During the Plenary Scientific Session on Sunday, Daniel Wolff, MD, shared encouraging results of the AGAVE-201 trial of axatilimab, an anti–CSF-1R monoclonal antibody, shown to be safe and effective in reducing chronic graft-versus-host disease (cGVHD) in heavily pre-treated patients. Perhaps the most surprising outcome of this global, phase II trial was that the lowest dose cohort experienced the least toxicity and highest overall response rate. Identifying novel treatment strategies for GVHD allows for further expansion of the indications for transplant with alternative donor options. 

During the Late-Breaking Abstracts Session, the ever-enthusiastic, Adetola Kassim, MD, MS, presented the promising results from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 1507 trial of reduced intensity haploidentical BMT with post-transplant cyclophosphamide (PTCy) in adults with severe sickle cell disease. It concluded that haploidentical BMT with PTCy was suitable, tolerable, and ultimately comparable to matched sibling donor transplants with myeloablative conditioning. These results are critical, revealing a potential curative option for patients with sickle cell disease who might be otherwise ineligible for gene therapy trials.  

Though we have yet to reach the limits of this vast frontier, there has been so much explored, with pioneers found everywhere you look. Yesterday afternoon, Ali Bazarbachi, MD, PhD, using the European Society for Blood and Marrow Transplantation registry data, detailed the “impressive” improvement over time in post-transplant outcomes for older acute myeloid leukemia (AML) patients (>65 years old) with decreased cumulative incidence of relapse and improved leukemia-free survival, overall survival, and (GVHD)-free, relapse-free survival (GRFS). Improved outcomes for older patients as time goes on is at least partly linked to advancements in transplantation, such as PTCy. During the same session (Allogenic Transplantation: Disease Response and Comparative Treatment Studies: Modern Challenges in Transplantation), Shernan G. Holtan, MD, shared results from the quality-of-life study component of the BMT CTN 1703 (a randomized phase III trial of PTCy, tacrolimus, and mycophenolate mofetil versus tacrolimus/methotrexate for GVHD prophylaxis) that showed superior GRFS in the PTCy-containing arm. In addition to confirming superior GFRS for the PTCy regimen, this study also demonstrated better patient-reported outcomes with PTCy. With the clinical success of PTCy, there are ongoing efforts to determine optimal dosing for patients. On Sunday, Hang Zhang, MD, presented a phase I/II PTCy dose de-escalation trial in stem cell transplants with HLA-identical donors and revealed that a two-day regimen of PTCy at 25 mg/kg/day was an effective and safe prophylactic measure against acute GVHD.  

Delving deeper into the expanse of the TCT frontier, chimeric antigen receptor (CAR) T-cell therapies have now been successfully translated from bench to bedside, particularly in B-cell malignancies and multiple myeloma. However, successes in CAR T-cell therapy for AML remain elusive. The absence of targetable and unique surface antigens on AML cells makes designing CAR T-cells challenging. During Monday’s Oral Abstract Session on Cellular Immunotherapies: Basic and Translational: Innovative T Cell Therapies for Unexplored Frontiers, Jort J Van Der Schans, MSc, from the Netherlands presented a novel and promising approach to CAR T in AML, utilizing dual-split CAR T-cells targeting CLEC12a and TIM3, ultimately demonstrating robust anti-AML activity. Another avenue of progress in the realm of CAR T-cell therapy is the ongoing development of invariant Natural Killer T (iNKT)-cell therapy, with one such effort presented by Hongwei Ren, MD. Dr. Ren detailed the pre-clinical success of a bispecific CAR-iNKT in treating MLL-rearranged acute lymphoblastic leukemia (ALL). 

I think it is entirely possible that transplant and cellular therapy is, in fact, the final frontier. And as the field boldly goes where none have gone before, it is impossible to highlight all the tremendous scientific achievements covered during this year’s program. In addition to those highlighted above, be sure to check out the following abstracts illuminating novel explorations into uncharted frontiers: “Apamistamab-led Allogenic Hematopoietic Cell Transplant Significantly Improves Overall Survival in Patients With TP53 Mutated R/R AML” and “Phase ½ Dose-escalation/Dose-expansion Study of Anti-CD7 Allogenic Cart-T Cells (WU-CART-007) in Relapsed or Refractory (R/R) T-Cell Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma (T-ALL/LBL).” Now if you don’t mind, I’ve got to put my helmet on … commencing countdown, engines on ... 

Dr. Ragon indicated no relevant conflicts of interest. 


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