Novel T-Cell Engineering Strategy Aims to Reduce GVHD in Lymphoma Transplantations

Vaishalee Kenkre, MD

Assistant Professor of Medicine

Division of Hematology and Oncology

There are few efficacious treatment options for patients with Hodgkin lymphoma and aggressive non-Hodgkin lymphoma who have previously failed autologous stem cell transplant (ASCT) or who are ineligible for ASCT due to progressive disease. There are also limited options for patients with indolent lymphomas who have suffered multiple relapses. In both of these patient populations, there is a need for novel and ideally curative options.

Allogeneic hematopoietic cell transplantation has been studied in lymphoma, both in aggressive histologies^1-9 and indolent histologies.^10-14 Studies support a potential for graft-versus-lymphoma (GVL) effect, though often at the cost of significant treatment-related morbidity and mortality. Complications often arise as a result of graft-versus-host disease (GVHD).

While rates of acute GVHD with reduced-intensity conditioning regimens may range relatively lower (10% to 20%), rates of extensive chronic GVHD range from 45% to 60%, even with human leukocyte antigen (HLA) matched donors.^{13, 14}

Additionally, standard practice involves identifying a sibling who is an HLA-match, and if not available, searching for an unrelated donor, which can delay or even negate the possibility of transplant for such patients. The optimal scenario would be one in which GVL could be optimized while minimizing GVHD, and donors could be identified quickly.

Our pilot trial, to our knowledge, is the first of its type to investigate T cell receptor alpha/beta (TCRa/β)-depleted and CD19-depleted haploidentical stem cell grafts in relapsed/refractory lymphoma patients. We hypothesize that TCRa/β and CD19 depletion from haploidentical stem cell grafts in patients with relapsed/refractory lymphoma will lead to successful engraftment along with lower rates of acute and chronic GVHD than typically seen after matched donor transplantation in lymphoma patients, and ultimately a long lasting GVL effect.

TCRa/β cells and B cells are thought to be major players in mediation of GVHD. Selective removal of these cells from the transplanted graft would minimize GVHD, while still allowing for a meaningful GVL effect (from TCRγ/δ cells and other important mediating cell types).

First clinical experiences in TCRa/β-depleted and CD19-depleted PBSC grafts have been obtained in haploidentical transplantation with pediatric patients in Tübingen.^15,16 All patients were at extremely high risk and had poor prognosis. They were pretreated with a reduced-intensity conditioning (RIC) regimen and received no post-transplantation immunosuppression. In these pilot patients, engraftment and immune reconstitution were rapid. No acute side-effects were noted. Similar small studies, primarily in pediatrics and conducted in Europe, have replicated similar data.

There is growing evidence that haploidentical donor transplants (primarily using post-transplant cyclophosphamide as immunosuppression) may be just as efficacious, if not more so, than matched unrelated donor transplants for adult patients with lymphoma.¹⁷

Furthermore, in aggressive lymphomas, even data with matched related donor transplants is not highly promising,^18-20 and the use of haploidentical donors is even more compelling and potentially associated with better disease control and less GVHD.²¹

Additionally, haploidentical donors are typically readily available. In theory, virtually every patient has a potentially suitable haploidentical related donor—parent, sibling, or child—and thus a successful strategy for haploidentical donor transplantation may clearly be the solution for the ‘lacking donor’ problem.

Although preliminary data with TCRa/β - and CD19-depleted haploidentical graft transplantation is promising, any data with this type of graft manipulation in patients with lymphoma, while highly warranted, is lacking.

We have developed a novel clinical protocol including a new conditioning regimen. Our clinical cell processing laboratory at University of Wisconsin Hospital and Clinics has validated the depletion strategy being used for this study and is one of the first in the country capable of providing this for clinical use.

Figure 1. Proposed Treatment Schema

Our trial is open to patients with relapsed/refractory Hodgkin lymphoma, diffuse large B cell lymphoma, follicular lymphoma, small lymphocytic lymphoma/chronic lymphocytic leukemia, mantle cell lymphoma, and T cell lymphoma. They will receive fludarabine/cyclophosphamide/ total nodal irradiation conditioning followed by transplantation of a haploidentical stem cell product that has undergone TCRa/β - and CD19-depletion (see Figure 1).Although the primary endpoint for the study is engraftment of neutrophils and platelets by day 28, the incidence of acute and chronic GVHD and progression-free survival and overall survival are all included as secondary endpoints. Additionally, patients will have a detailed and highly sophisticated immunophentypic analysis by flow cytometry of peripheral blood lymphocytic populations at various time points after transplant to look for correlation to disease response, graft versus host disease, infection rates, and other potential side effects.

The study is now IRB approved and open to accrual with an IDE from the FDA. Please obtain more details at: https://clinicaltrials. gov/ct2/show/NCT02652468If you have patients potentially eligible for this trial, please contact us at 608-263-1699 or vpkenkre@medicine.wisc.edu.

References

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