Subclonal Evolution of Chronic Lymphocytic Leukemia After Allogeneic T Cell Therapies

<p><strong>Subclonal evolution of chronic lymphocytic leukemia after allogeneic T-cell therapies</strong></p> <p>Haven Garber, MD</p> <p>Advisory Professor: Jeffrey Molldrem, MD</p> <p>Intratumoral genetic heterogeneity describes the molecular differences among subclones within a tumor and is a major barrier to effective therapy in many solid and liquid cancers, including chronic lymphocytic leukemia (CLL). Rare, treatment-resistant subclones can expand to compose relapsed disease during tumor evolution. Examination of malignant evolution in the context of specific treatment provides insight into the molecular lesions that mediate therapeutic response and resistance. Both chemotherapy and targeted therapy were shown to precipitate CLL subclonal evolution. We hypothesized that allogeneic T-cell immunotherapies, including allogeneic stem cell transplant (alloSCT) and donor lymphocyte infusion (DLI), would impact malignant evolution through the application of selective immunologic pressure imposed by donor T cells. Here, we tested this prediction in a cohort of 24 CLL patients treated with nonmyeloablative HLA-matched alloSCT and DLI utilizing whole exome sequencing of purified CLL. Our cohort included 11 patients who relapsed after alloSCT, and we studied sequential samples in these patients to examine leukemic evolution. We identified clear patterns of linear and branched evolution in 8/11 patients after alloSCT/DLI that included CLL-specific drivers in every case. In two patients, leukemic evolution was coincident with DLI, suggesting immunoediting of leukemic subclones. To investigate complementary changes in immunity, we analyzed the post-alloSCT T cell repertoires of CLL transplant recipients at multiple time points after engraftment and observed restricted diversity. Last, we adapted and employed a strategy to identify and track candidate graft-versus-leukemia T cells that expanded and contracted coincident with loss of specific tumorigenic lesions. We provide novel evidence of ongoing genetic subclonal evolution of CLL post-alloSCT.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2020

Authors dc:creator

• Garber, Haven
• <p>0000-0002-8221-2167</p>

Contributors dc:contributor

• Jeffrey J. Molldrem, MD
• R. Eric Davis, MD
• P. Andrew Futreal, PhD

• allogeneic stem cell transplant
• chronic lymphocytic leukemia
• subclonal evolution
• intratumoral heterogeneity
• neoantigen
• t cell repertoire
• graft versus leukemia effect
• single T cell TCR sequencing
• Cancer Biology
• Immunotherapy
• Medicine and Health Sciences

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1044

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2097