Cellular immunotherapy was featured prominently during ASH 2020, with many presentations detailing deep and durable responses in a range of hematologic malignancies, mostly large B-cell lymphoma.
Making cellular therapies and stem-cell transplant more accessible was the focus of the ASH Presidential Symposium, during which presenters spoke of potential universal donor solutions to reduce the cost and increase access to cellular immunotherapy.
The potency of chimeric antigen receptor (CAR) T-cell therapy was improved dramatically with the development of second-generation CAR T-cell therapy, which has become the mainstay of treatment for B-cell malignancies, said Gay M. Crooks, MBBS, Co-Director, UCLA Broad Stem Cell Research Center, University of California, Los Angeles. The great advantage to relying on autologous T-cells is human leukocyte antigen (HLA) matching, she said.
“But there are many disadvantages involving the logistics and the clinical coordination that limit access for all patients to care, and cause enormous recurring costs because of the vectors that are used, the pheresis, and the manufacturing that has to be done de novo each time,” said Dr Crooks. “And importantly, the cell products developed have an inconsistency built into them because they are patient-specific.”
Next-generation approaches to cell therapies include the use of nonrenewable types of cells (ie, healthy donor) and renewable source of cells (ie, from pluripotent stem cells).
The use of natural killer (NK) cells for these types of therapies does not expose the patient to the risk for graft-versus-host disease (GVHD), but NK cells can be rejected by the host because of major histocompatibility complex mismatch. NK cells also do not persist as long in their normal biologic state as T-cells.
T-cells will need to be engineered to be able to avoid rejection and GVHD, and to provide antitumor specificity.
“But the great opportunity here is to manipulate function,” said Dr Crooks.
The jury is still out on the source of allogeneic cells for off-the-shelf therapy. The use of healthy donor NK cells and peripheral blood T-cells is intriguing; each can provide mature functional cells and produce multiple products per donation, but they are not self-renewing and require complex editing that is problematic, because of translocations with multiple edits, Dr Crooks said.
The use of pluripotent stem cells has great potential for gene manipulation, particularly through editing. By their nature, pluripotent stem cells are self-renewing, and allow complex gene editing and indefinite expansion. Pluripotent stem cells, however, have the downside of a complex differentiation process.
Donor registries are helping to overcome one of the challenges involved in finding suitable healthy donors for allogeneic stem-cell transplant, said Bronwen E. Shaw, MD, PhD, MRCP, Professor of Hematology and Oncology, Medical College of Wisconsin, Milwaukee.
Although transplant outcomes are still superior when using HLA-matched donors (ie, siblings or unrelated donors), outcomes are acceptable and improving when using mismatched donors, she said.
“The use of HLA-mismatched donors provides previously underserved patients with a transplant option,” said Dr Shaw.
The World Marrow Donor Association has created a central mechanism by which the HLA types of donors are shared. It represents 135 registries in 55 countries, and lists more than 38 million volunteer unrelated donors.
“This is really important, because the percentage of stem-cell products that cross an international border has gone from 30% to currently 50%, meaning that half of your patients will have had their product cross an international border,” she said.
The large number of unrelated donor transplants and precision matching has enabled studies that show superior survival when using an HLA-matched unrelated donor, leading to prioritization of HLA-identical donors.
The applicability of using haploidentical donors has been boosted by the use of cyclophosphamide in the posttransplant setting to modulate the immune system. Recent data show continued improved survival of haploidentical transplant using posttransplant cyclophosphamide, “suggesting we are able to get better at this technique as we understand it more,” said Dr Shaw.
Most recently, in a phase 2 prospective clinical trial, using a mismatched donor and posttransplant cyclophosphamide resulted in a 1-year survival rate of >65%, with approximately 50% of the patients who had transplant in the study being from ethnically diverse backgrounds.
Stella Chou, MD, Attending Physician, Division of Hematology and the Apheresis Program, Children’s Hospital of Philadelphia, PA, closed the symposium by presenting evidence demonstrating that gene editing of induced pluripotent stem cells can generate universal red cell and platelet products.