A new T-cell immunotherapy is showing promise in preventing the risk of relapse of leukemia following allogeneic hematopoietic stem cell transplantation (HSCT), and the results have led to the launch of a first-in-human clinical trial of the approach, which relies on engineered T-cell receptors (TCRs).
HSCT, which plays a key role in treating many types of leukemia, is generally effective in preventing relapse compared with use of chemotherapy alone. However, relapse still occurs in approximately one-third of patients who undergo the procedure, and only a small percentage of those patients survive. New therapies are therefore needed to prevent and treat relapse in patients who have undergone HSCT.
There is compelling evidence that potent selective anti-leukemic effects can be delivered by donor T cells specific for particular minor histocompatibility antigens. TCRs isolated from minor histocompatibility antigen-specific T cells represent an untapped resource for developing targeted T-cell immunotherapy to manage post-HSCT leukemic relapse.
As described in the study published in Blood, the novel form of immunotherapy was developed by a team led by Marie Bleakley, MD, PhD, of Fred Hutchinson Cancer Research Center and the University of Washington in Seattle. The treatment is comprised of memory T cells transduced with a lentiviral vector encoding a transgene with several elements:
- TCR targeting a leukemia-associated minor histocompatibility antigen, HA-1
- A CD8 co-receptor that allows the TCR to function in CD4 helper T cells
- A safety-switch/suicide gene that allows researchers to turn the T cells off in the event of excessive toxicity
- A selection tag to enrich and track the cells
“The introduction of CD8 co-receptors into CD4 T cells has previously been studied in several labs, but as far as we know this is the first time it will be studied in a clinical trial,” Bleakley told MedPage Today. “One of the slightly surprising, but very positive, aspects of the study is that we were able to incorporate multiple desirable elements into the vector and successfully deliver them to the T cells, enabling the T cells to specifically kill human leukemia and also express the safety and feasibility features.”
The engineered T-cell immunotherapy differs from chimeric antigen receptor (CAR) T-cell therapies, she explained. TCR T-cell immunotherapy and CAR T-cell immunotherapy are both forms of genetically engineered T-cell immunotherapy, but they differ in that CAR T-cell immunotherapy employs synthetic receptors with an antibody-like binding element for antigen recognition. “To create TCR T-cell immunotherapy we transfer natural TCRs that are found in the blood or tissues from one individual to T cells belonging to other people.”
CAR T-cell therapy is highly effective for treating CD19+ B-lineage acute lymphoblastic leukemia (ALL) even in the post-HSCT setting, but novel T-cell immunotherapies are required for patients with other leukemia types. “An advantage of TCR T-cell immunotherapy is that it is not limited to the recognition of cell surface molecules,” Bleakley noted. “TCRs respond to small protein fragment ‘peptides’ that can be derived from proteins in the cells, or on the surface. This really opens up the options for targets, and can provide excellent specificity.”
This T-cell immunotherapy holds clinical promise for multiple types of leukemia, she continued: “It may be a new immunotherapy suitable for treating, and ultimately preventing, relapse of acute myeloid leukemia, B-lineage ALL, or T-lineage ALL, in patients with a specific genotype. HA-1 TCR T-cell immunotherapy is suitable for managing relapse only in the context of allogeneic HSCT because it requires a specific genetic difference between donors and recipients. However, the post-HSCT setting might provide some unique advantages in amplifying the effectiveness of the antigen-specific T-cell immunotherapy. Ultimately, we may incorporate the TCR T cells into the stem cell graft — that is, a highly engineered stem cell graft, augmented for a potent ‘graft-versus-leukemia’ effect.”
If the HA-1 TCR immunotherapy is successful in clinical trials, it will serve as a proof of principle for a class of leukemia-associated antigens. The introduction of a CD8 co-receptor into CD4 T cells — providing CD4 T cell function and help for HA-1-specific CD8s by allowing the class I restricted TCR to function effectively in CD4 T cells — has not been studied in clinical trials before, Bleakley said, adding that an upcoming clinical trial may provide the first proof of concept of CD8 co-receptors in TCR T-cell immunotherapy.
A phase I clinical trial for both children and adults with ALL or acute myeloid leukemia who are relapsing or predicted to relapse after HSCT is scheduled to be conducted at Fred Hutchinson, and should be open to patient enrollment by early 2018, she said.
Practicing oncologists should be aware of the HA-1 TCR T-cell immunotherapy as a potential option for patients who are relapsing, or at risk of relapsing, after HSCT, Bleakley added: “Oncologists need to be aware of the increasing number of T-cell immunotherapy options, beyond CD19 CAR T cells, for patients with leukemia and other cancers. If they have patients in need, it is worth re-checking the current options.”