Dissecting the mechanistic basis of response to combined decitabine and ipilimumab following hematopoietic stem cell transplantation for relapsed acute myelogenous leukemia
Final Report Abstract
Relapse of acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (HSCT) remains an unresolved clinical challenge and novel therapeutic approaches are urgently needed to improve long-term survival. In recent years, immune checkpoint blockade (ICB) has been recognized as a strategy to improve post-transplant outcomes by reinstating a graft-versus-leukemia (GvL) response and to achieve renewed disease control following relapse. However, the mechanisms how ICB, for example using the CTLA-4 blocking antibody ipilimumab or through PD-1 inhibition with nivolumab, can reawaken GvL remain incompletely understand. With the availability of high-throughput bulk and single cell sequencing platforms as well as lineage-tracing approaches it is now possible to dissect the mechanistic basis of responses to immunotherapies for leukemic relapse after transplant more deeply. During the funding period of the research scholarship, I made use of these technical innovations and thus worked on the following projects: By leveraging primary peripheral blood and bone marrow samples collected from study participants of the ETCTN/CTEP 9204 and 10026 trials that tested ipilimumab monotherapy (9204) or combined decitabine and ipilimumab treatment (10026) for relapsed AML after transplant, I performed detailed characterizations of the pharmacodynamics of ipilimumab in the post-transplant setting and identified predictors of response to this treatment. Using a dense sample collection of peripheral blood samples obtained from an exceptional responder to PD-1 inhibition with relapsed secondary JAK2V617F+ AML post-HSCT before, during and after therapy, I performed an integrative analysis using different DNA-, RNA- and proteinbased single cell technologies. I could show the complementary nature of these platforms and traced the co-evolution of donor T cells and AML blasts underlying transient response to and progression following nivolumab treatment . Finally, I adopted a novel single cell lineage-tracing approach based on mitochondrial DNA mutations that permits to link genotype to chromatin state. With this technology, I traced leukemic evolution before and after therapeutic bottlenecks including stem cell transplantation and demonstrated that it can also be used for murine models of human leukemia . Together, these projects provide a framework for future single cell investigations of immune and leukemic cell interactions in the context of allogeneic stem cell transplantation that I envision as follow-up studies to this research fellowship.
Publications
- Personal tumor antigens in blood malignancies: genomics-directed identification and targeting JCI. 130 (4), 1595-1607
Penter L, Wu CJ
(See online at https://doi.org/10.1172/jci129209) - Coevolving JAK2V617F+ relapsed AML and donor T cells with PD-1 blockade after stem cell transplantation: an index case Blood Advances. 5(22):4701-4709
Penter L, Gohil SH, Huang T, Thrash EM, Schmidt D, Li S, Severgnini M, Neuberg DS, Hodi FS, Livak KJ, Zeiser R, Bachireddy P, Wu CJ
(See online at https://doi.org/10.1182/bloodadvances.2021004335) - Longitudinal single-cell dynamics of chromatin accessibility and mitochondrial mutations in chronic lymphocytic leukemia mirror disease history Cancer Discovery
Penter L, Gohil SH, Lareau C, Ludwig LS, Parry EM, Huang T, Li S, Zhang W, Livitz D, Leshchiner I, Parida L, Getz G, Rassenti LZ, Kipps TJ, Brown JR, Davids MS, Neuberg DS, Livak KJ, Sankaran VG, Wu CJ
(See online at https://doi.org/10.1158/2159-8290.cd-21-0276) - Molecular and cellular features of CTLA-4 blockade for relapsed myeloid malignancies after transplantation Blood. 137 (23), 3212-3217
Penter L, Zhang Y, Savell A, Huang T, Cieri N, Thrash EM, Kim-Schulze S, Jhaveri A, Fu J, Ranasinghe S, Li S, Zhang W, Hathaway ES, Nazzaro M, Kim HT, Chen H, Thurin M, Rodig SJ, Severgnini M, Cibulskis C, Gabriel S, Livak KJ, Cutler C, Antin JH, Nikiforow S, Koreth J, Ho VT, Armand P, Ritz J, Streicher H, Neuberg D, Hodi FS, Gnjatic S, Soiffer RJ, Liu XS, Davids MS, Bachireddy P, Wu CJ
(See online at https://doi.org/10.1182/blood.2021010867) - Improved T cell immunity following neoadjuvant chemotherapy in ovarian cancer-Clin. Cancer Res.
Liu M, Tayob N, Penter L, Sellars M, Tarren A, Chea VA, Carulli I, Huang T, Li S, Cheng S-C, Le P, Frackiewicz L, Fasse J, Qi CH, Liu JF, Stover EH, Curtis J, Livak KJ, Neuberg DS, Zhang GL, Matulonis UA, Wu CJ, Keskin DB, Konstantinopoulos PA
(See online at https://doi.org/10.1158/1078-0432.CCR-21-2834) - Natural Barcodes for Longitudinal Single Cell Tracking of Leukemic and Immune Cell Dynamics Frontiers in Immunology. 12:788891
Penter L, Gohil SH, Wu CJ
(See online at https://doi.org/10.3389/fimmu.2021.788891)
