Research Summary

As a physician-scientist and member of the Hematological Malignancies and Stem Cell Transplantation Program and Helen Diller Family Cancer Center at UCSF, my clinical focus has been the treatment of hematological malignancies, combining chemotherapeutic and autologous or allogeneic bone marrow/ stem cell transplantation approaches. My laboratory has focused on the development of gene transfer and stem cell transplantation approaches for the treatment of hematologic disorders, with a current focus on the development of immunotherapeutic approaches to treat minimal residual disease (MRD) in older patients with acute myelogenous leukemia (AML). There is a major clinical unmet need for effective and safe therapies to increase progression-free and overall survival in older individuals with leukemia whose prognosis is grim.
Compelling evidence for the efficacy of immunotherapy in eliminating minimal residual disease (MRD) is provided by the superior outcomes of allogeneic hematopoietic stem cell transplants (HSCT) due to graft vs leukemia (GVL) effects. However, patients > 60 yo are often ineligible for allo-HSCT. Two vaccine approaches are being developed as part of a collaborative consortium at UCSF, UCLA, UC Davis, and King’s College, London.
Our vaccine project focuses on genetic engineering of autologous whole cell AML vaccines to express CD80, and IL-15, and IL-15 Receptor alpha (IL-15Rα). The leukemia-specific cytolytic activity stimulated by engineered, irradiated AML cell vaccines expressing IL-15/IL-15Ra/CD80 was tested in the murine 32Dp210 myeloid leukemia model that recapitulates many features of human AML. Proof of concept (POC) studies showed that treatment of leukemia-bearing hosts induced superior anti-leukemic immunity when compared with vaccines expressing either CD80, or IL15-IL15Rα alone and eradicated leukemia 80% in leukemic mice an effect mediated by CD8+ T cells. (Shi, Y. et al (2018)).
Based on these proof of concept studies we received a Catalyst award through the CTSI at UCSF, a Translational Research Program grant from the Leukemia and Lymphoma Society in 2017, and a CIRM Translational-1 grant in 2018 to pursue non-overlapping studies with cGMP reagents supporting submission of a Pre-IND package to the FDA. Most recently, we were awarded a CIRM CLIN 1 grant (12/2022)to pursue IND enabling studies. These studies are being pursued as part of a collaborative consortium with investigators at UCSF (M. Rosenblum, L. Damon, A. Nambiar, A.Combes and K. Ganapathi), UCLA (Donald Kohn), and King's College London (Farzin Farzaneh).

Research Funding

  • February 1, 2018 - January 31, 2023 - Developing Engineered Autologous Leukemia vaccines to Target Residual Leukemic Stem Cells , PI . Sponsor: CIRM TRAN-1, Sponsor Award ID:
  • October 1, 2017 - September 30, 2022 - Inducing effective anti-leukemic immunity with novel AML vaccines expressing IL15/IL-15Ra/CD80 , PI . Sponsor: Leukemia Lymphoma Society, Sponsor Award ID:
  • December 1, 2011 - November 30, 2015 - Lentivirus-based positive/negative selection in minimally ablative transplants , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01HL107974
  • August 6, 2013 - July 31, 2015 - Efficacy and safety of novel CD80 IL15 IL15Ra expressing autologous AML vaccines , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R21CA177284

Education

Swarthmore College, Swarthmore, PA, B.A., 1977, Biology
Harvard Medical School, M.D., 1981, Medicine
Univ of California, San Francisco, CA, Resident, 1981-84, Internal Medicine
Univ of California, San Francisco, CA, Fellow, 1984-87, Hematology/Oncology

Honors & Awards

  • 1988-1990
    American Cancer Society Fellowship
  • 1991-1992
    Howard Hughes Medical Institute Fellowship
  • 1992-1997
    NIH Physician Scientist Award

Selected Publications

  1. Huang LW, Sheng Y, Andreadis C, Logan AC, Mannis GN, Smith CC, Gaensler KML, Martin TG, Damon LE, Huang CY, Olin RL. Patterns and Predictors of Functional Decline after Allogeneic Hematopoietic Cell Transplantation in Older Adults. Transplant Cell Ther. 2022 06; 28(6):309.e1-309.e9.  View on PubMed
  2. Wang VE, Blaser BW, Patel RK, Behbehani GK, Rao AA, Durbin-Johnson B, Jiang T, Logan AC, Settles M, Mannis GN, Olin R, Damon LE, Martin TG, Sayre PH, Gaensler KM, McMahon E, Flanders M, Weinberg V, Ye CJ, Carbone DP, Munster PN, Fragiadakis GK, McCormick F, Andreadis C. Inhibition of MET Signaling with Ficlatuzumab in Combination with Chemotherapy in Refractory AML: Clinical Outcomes and High-Dimensional Analysis. Blood Cancer Discov. 2021 09; 2(5):434-449.  View on PubMed
  3. Huang LW, Sheng Y, Andreadis C, Logan AC, Mannis GN, Smith CC, Gaensler KML, Martin TG, Damon LE, Steinman MA, Huang CY, Olin RL. Functional Status as Measured by Geriatric Assessment Predicts Inferior Survival in Older Allogeneic Hematopoietic Cell Transplantation Recipients. Biol Blood Marrow Transplant. 2020 01; 26(1):189-196.  View on PubMed
  4. Wieduwilt MJ, Pawlowska N, Thomas S, Olin R, Logan AC, Damon LE, Martin T, Kang M, Sayre PH, Boyer W, Gaensler KML, Anderson K, Munster PN, Andreadis C. Histone Deacetylase Inhibition with Panobinostat Combined with Intensive Induction Chemotherapy in Older Patients with Acute Myeloid Leukemia: Phase I Study Results. Clin Cancer Res. 2019 08 15; 25(16):4917-4923.  View on PubMed
  5. Shi Y, Dincheva-Vogel L, Ayemoba CE, Fung JP, Bergamaschi C, Pavlakis GN, Farzaneh F, Gaensler KML. IL-15/IL-15Rα/CD80-expressing AML cell vaccines eradicate minimal residual disease in leukemic mice. Blood Adv. 2018 11 27; 2(22):3177-3192.  View on PubMed
  6. Greenberg PL, Stone RM, Al-Kali A, Barta SK, Bejar R, Bennett JM, Carraway H, De Castro CM, Deeg HJ, DeZern AE, Fathi AT, Frankfurt O, Gaensler K, Garcia-Manero G, Griffiths EA, Head D, Horsfall R, Johnson RA, Juckett M, Klimek VM, Komrokji R, Kujawski LA, Maness LJ, O'Donnell MR, Pollyea DA, Shami PJ, Stein BL, Walker AR, Westervelt P, Zeidan A, Shead DA, Smith C. Myelodysplastic Syndromes, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2017 01; 15(1):60-87.  View on PubMed
  7. Mannis GN, Martin TG, Damon LE, Andreadis C, Olin RL, Kong KA, Faham M, Hwang J, Ai WZ, Gaensler KML, Sayre PH, Wolf JL, Logan AC. Quantification of Acute Lymphoblastic Leukemia Clonotypes in Leukapheresed Peripheral Blood Progenitor Cells Predicts Relapse Risk after Autologous Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant. 2016 06; 22(6):1030-1036.  View on PubMed
  8. Mannis GN, Martin TG, Damon LE, Logan AC, Olin RL, Flanders MD, Ai WZ, Gaensler KM, Kaplan LD, Sayre PH, Smith CC, Wolf JL, Andreadis C. Long-term outcomes of patients with intermediate-risk acute myeloid leukemia treated with autologous hematopoietic cell transplant in first complete remission. Leuk Lymphoma. 2016 07; 57(7):1560-6.  View on PubMed
  9. Ikuta T, Sellak H, Odo N, Adekile AD, Gaensler KM. Nitric Oxide-cGMP Signaling Stimulates Erythropoiesis through Multiple Lineage-Specific Transcription Factors: Clinical Implications and a Novel Target for Erythropoiesis. PLoS One. 2016; 11(1):e0144561.  View on PubMed
  10. Li B, Luo X, Deng B, Wang J, McComb DW, Shi Y, Gaensler KM, Tan X, Dunn AL, Kerlin BA, Dong Y. An Orthogonal Array Optimization of Lipid-like Nanoparticles for mRNA Delivery in Vivo. Nano Lett. 2015 Dec 09; 15(12):8099-107.  View on PubMed
  11. Tye GJ, Ioannou K, Amofah E, Quartey-Papafio R, Westrop SJ, Krishnamurthy P, Noble A, Harrison PM, Gaensler KML, Barber LD, Farzaneh F. The combined molecular adjuvant CASAC enhances the CD8+ T cell response to a tumor-associated self-antigen in aged, immunosenescent mice. Immun Ageing. 2015; 12:6.  View on PubMed
  12. Greenberg PL, Stone RM, Bejar R, Bennett JM, Bloomfield CD, Borate U, De Castro CM, Deeg HJ, DeZern AE, Fathi AT, Frankfurt O, Gaensler K, Garcia-Manero G, Griffiths EA, Head D, Klimek V, Komrokji R, Kujawski LA, Maness LJ, O'Donnell MR, Pollyea DA, Scott B, Shami PJ, Stein BL, Westervelt P, Wheeler B, Shead DA, Smith C, National comprehensive cancer network. Myelodysplastic syndromes, version 2.2015. J Natl Compr Canc Netw. 2015 Mar; 13(3):261-72.  View on PubMed
  13. Mannis GN, Andreadis C, Logan AC, Damon LE, Benet LZ, Ai WZ, Gaensler KM, Kaplan LD, Koplowicz YB, Linker CA, Olin RL, Sayre PH, Smith CC, Sudhindra A, Venstrom JM, Wolf JL, Martin TG. A phase I study of targeted, dose-escalated intravenous busulfan in combination with etoposide as myeloablative therapy for autologous stem cell transplantation in acute myeloid leukemia. Clin Lymphoma Myeloma Leuk. 2015 Jun; 15(6):377-83.  View on PubMed
  14. Barzel A, Paulk NK, Shi Y, Huang Y, Chu K, Zhang F, Valdmanis PN, Spector LP, Porteus MH, Gaensler KM, Kay MA. Promoterless gene targeting without nucleases ameliorates haemophilia B in mice. Nature. 2015 Jan 15; 517(7534):360-4.  View on PubMed
  15. Mannis GN, Logan AC, Leavitt AD, Yanada M, Hwang J, Olin RL, Damon LE, Andreadis C, Ai WZ, Gaensler KM, Greene CC, Gupta NK, Kaplan LD, Mahindra A, Miyazaki Y, Naoe T, Ohtake S, Sayre PH, Smith CC, Venstrom JM, Wolf JL, Caballero L, Emi N, Martin TG. Delayed hematopoietic recovery after auto-SCT in patients receiving arsenic trioxide-based therapy for acute promyelocytic leukemia: a multi-center analysis. Bone Marrow Transplant. 2015 Jan; 50(1):40-4.  View on PubMed
  16. Keller JW, Andreadis C, Damon LE, Kaplan LD, Martin TG, Wolf JL, Ai WZ, Venstrom JM, Smith CC, Gaensler KM, Hwang J, Olin RL. Hematopoietic cell transplantation comorbidity index (HCT-CI) is predictive of adverse events and overall survival in older allogeneic transplant recipients. J Geriatr Oncol. 2014 Jul; 5(3):238-44.  View on PubMed
  17. Shi Y, Falahati R, Zhang J, Flebbe-Rehwaldt L, Gaensler KM. Role of antigen-specific regulatory CD4+CD25+ T cells in tolerance induction after neonatal IP administration of AAV-hF.IX. Gene Ther. 2013 Oct; 20(10):987-96.  View on PubMed
  18. Ito M, Ohba S, Gaensler K, Ronen SM, Mukherjee J, Pieper RO. Early Chk1 phosphorylation is driven by temozolomide-induced, DNA double strand break- and mismatch repair-independent DNA damage. PLoS One. 2013; 8(5):e62351.  View on PubMed
  19. Falahati R, Zhang J, Flebbe-Rehwaldt L, Shi Y, Gerson SL, Gaensler KM. Chemoselection of allogeneic HSC after murine neonatal transplantation without myeloablation or post-transplant immunosuppression. Mol Ther. 2012 Nov; 20(11):2180-9.  View on PubMed
  20. Mintz PJ, Sætrom P, Reebye V, Lundbæk MB, Lao K, Rossi JJ, Gaensler KM, Kasahara N, Nicholls JP, Jensen S, Haoudi A, Emara MM, Gordon MY, Habib NA. MicroRNA-181a* Targets Nanog in a Subpopulation of CD34(+) Cells Isolated From Peripheral Blood. Mol Ther Nucleic Acids. 2012 Aug 07; 1:e34.  View on PubMed

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