Novel immunotherapeutical strategies in allogeneic hematopoietic stem cell transplantation

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the most potent immunotherapeutic measure used in clinical practice. This thesis deals with three problems related to allo-HSCT. Firstly, often no suitable donor is available for patients who need allo-HSCT and the use of umbilical cord blood (UCB) as a source of stem cells is one solution. The feasibility of this alternative is examined in paper I, and drawbacks of this approach are addressed in papers II and III. Secondly, allo-HSCT is an established therapy for hematological malignancies and a complementary treatment for metastatic solid tumors. A very important effector mechanism of allo-HSCT, the graft-versus-tumor (GVT) effect, comes hand in hand with the allogeneic reaction of the donor immune system to the host: so-called graft-versus-host disease (GVHD). GVHD is also one of the most fatal complications after allo-HSCT, which poses an immediate problem for successful management of the patient. Papers II and IV contribute to the studies of GVT and its differentiation from GVHD. Lastly, morbidity and mortality due to infections are substantial after allo-HSCT, and Epstein-Barr virus-associated post-transplant lymphoproliferative disease (EBV PTLD) is a condition for which effective treatment is sometimes lacking. Paper III presents a novel therapeutic approach to this problem.

In paper I, we compared the outcomes of allo-HSCT when using a human leukocyte antigen (HLA)- mismatched unrelated donor (MM URD) or UCB. We showed that UCB recipients had a significantly higher probability of survival than MM URD recipients and, consistent with reports from others, engraftment was significantly delayed after UCB transplantation (UCBT). Our results have led us to continue with UCB as a stem cell source for patients lacking an HLA-identical donor.

One of the limitations of UCBT is the lack of subsequent access to the donor, which limits the possibility of the recipient receiving a donor lymphocyte infusion (DLI) for a threatening rejection or relapse of the underlying malignant disease. In paper II, we described a clinically feasible procedure for in vitro expansion of CB-derived T-lymphocytes for use as DLI. We also presented an analysis of the phenotype and repertoire of the expanded T cells and demonstrated their capacity to produce cytokines and to proliferate in response to stimulation.

UCBT is also associated with an increased risk of severe viral infections after transplantation. In paper III, we presented a novel approach for rapid isolation of EBV-specific cytotoxic T-cells (CTLs) from a haplo-identical donor. The EBV CTLs were administered to a female patient with a life-threatening EBV PTLD without complications, and they persisted in the patient and contributed to the clearance of the disease.

Allo-HSCT has not been described previously for prostate cancer. In paper IV, we showed a GVT effect in a prostate cancer patient after HSCT. We were also able to demonstrate the presence of functional prostate-specific CTLs in the patient, which were dormant in the female donor. These cells may be important in mediating a GVT effect.

In conclusion, the studies presented in this thesis demonstrate how a strong collaboration between clinical and basic research can lead to increased knowledge and possible treatment modalities for patients undergoing HSCT. The data presented may be of importance for further development of adoptive immunotherapy protocols for infections and malignancies after HSCT.

List of scientific papers

I. Ringdén O, Okas M, Uhlin M, Uzunel M, Remberger M, Mattsson J (2008). "Unrelated cord blood and mismatched unrelated volunteer donor transplants, two alternatives in patients who lack an HLA-identical donor." Bone Marrow Transplant 42(10): 643-8. Epub 2008 Sep 1
https://pubmed.ncbi.nlm.nih.gov/18762760

II. Okas M, Gertow J, Uzunel M, Karlsson H, Westgren M, Kärre K, Ringden O, Mattsson J, Uhlin M (2010). "Clinical expansion of cord blood-derived T cells for use as donor lymphocyte infusion after cord blood transplantation." J Immunother 33(1): 96-105
https://pubmed.ncbi.nlm.nih.gov/19952951

III. Uhlin M, Okas M, Gertow J, Uzunel M, Brismar TB, Mattsson J (2010). "A novel haplo-identical adoptive CTL therapy as a treatment for EBV-associated lymphoma after stem cell transplantation." Cancer Immunol Immunother 59(3): 473-7. Epub 2009 Nov 12
https://pubmed.ncbi.nlm.nih.gov/19908041

IV. Uhlin M, Okas M, Karlsson H, Gertow J, Henningsohn L, Ringdén O, Kärre K, Levitsky V, Mattsson J (2009). "Increased frequency and responsiveness of PSA-specific T cells after allogeneic hematopoetic stem-cell transplantation." Transplantation 87(4): 467-72
https://pubmed.ncbi.nlm.nih.gov/19307781