Stem cell engraftment in MHC-matched and mismatched transplants: development of nonmyeloablative conditioning regimens
Our primary goal is to develop conditioning regimens that have minimal toxicity and, thus, allow us to extend the benefit of stem cell transplants to a greater number of patients. Towards that end, we are using a preclinical model and have extended our findings to patients in clinical studies.
The long-term objective of the development of nonmyeloablative conditioning regimens is to extend the application of stem cell transplants to use in older patients and patients with nonmalignant diseases, in addition to patients with malignancies, by developing less toxic conditioning regimens that permit engraftment and prevent graft-versus-host disease (GVHD).
To address this goal, nonmyeloablative conditioning regimens for hematopoietic allografts are being studied in a preclinical model. Data indicate that MAbs directed towards CD3/TCR facilitate establishment of donor chimerism in preclinical MHC-identical related transplants in a low dose radiation model. In MHC-haploidentical transplants, data indicate that the anti-CD44 MAb S5 establishes donor engraftment in the low dose radiation model when given with standard immunosuppression.
Attempts to increase the dose of chemoradiotherapy to prevent relapse after transplant have been limited by toxicity to normal organs. Previously, we have carried out studies using emitting isotope-antibody conjugates (including I-131) to target the dose of radiation to the marrow and, thus, spare normal organs. Previously we have investigated the use of the alpha emitting radionuclide bismuth-213 (Bi-213)and our current studies are investigating the use of astatine-211 (At-211). The alpha emitters have the advantages of a relatively short half-life, high linear energy transfer, and are easier to handle than gamma emitters.
We have evaluated a Bi-213 anti-CD45 MAb conjugate for immunosuppression and have shown that this was sufficient conditioning for stable engraftment in the MHC-identical setting. We also have investigated the use of a Bi-213-anti-TCR MAb conjugate to target T cells to eliminate host-versus-graft (HVG) reactions in the MHC-identical setting and have had similar findings. Currently we are investigating this approach using At-211 in the MHC-identical and nonidentical setting.
Our current regimen for hematopoietic cell transplantation in human patients, developed in our preclinical model, uses a non-myeloablative conditioning regimen consisting of fludarabine and 2 Gy of total body irradiation before and mycophenolate mofetil combined with cyclosporine after transplant. This has now been successfully applied to patients with leukemia, lymphoma, multiple myeloma, and other malignant diseases who were too old or medically infirm to be eligible for conventional myeloablative transplants. Both related and unrelated HLA-identical donors are used. Data, thus far, indicate that successful allografts in patients otherwise ineligible for conventional allografting can be done with minimal toxicities.
Complete remissions including molecular remissions, have been seen in a substantial number of the patients, indicating that this approach is feasible and may be curative. We are also extending our findings to using donors that are not HLA-identical. Currently we are investigating the role of donor lymphocyte infusion (DLI) for both improvement of low donor chimerism and for treatment of persistent or relapsed disease.