Karin Gaensler, MD

HS CLIN PROF-HCOMP

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).

Publications

  1. Huang LW, Shi Y, Andreadis C, Logan AC, Mannis GN, Smith CC, Gaensler KML, Martin TG, Damon LE, Boscardin WJ, Steinman MA, Olin RL. Association of geriatric measures and global frailty with cognitive decline after allogeneic hematopoietic cell transplantation in older adults. Journal of geriatric oncology 2023. PMID: 37678052


  2. 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 alloHCT in older adults. 2022. PMID: 35247612


  3. 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 discovery 2021. PMID: 34514432


  4. 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 transplant recipients. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 2019. PMID: 31493541


  5. Wieduwilt MJ, Pawlowska N, Thomas S, Olin R, Logan AC, Damon LE, Martin T, Kang M, Sayre PH, Boyer W, Gaensler KM, 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. Clinical cancer research : an official journal of the American Association for Cancer Research 2019. PMID: 31152020


  6. Shi Y, Dincheva-Vogel L, Ayemoba CE, Fung JP, Bergamaschi C, Pavlakis GN, Farzaneh F, Gaensler KML. IL-15/IL-15Ra/CD80-expressing AML cell vaccines eradicate minimal residual disease in leukemic mice. Blood advances 2018. PMID: 30482760


  7. 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. Journal of the National Comprehensive Cancer Network : JNCCN 2017. PMID: 28040720


  8. 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. Volume 22 of Issue 6. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 2016. PMID: 26899561


  9. 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. Volume 57 of Issue 7. Leukemia & lymphoma 2016. PMID: 26490487


  10. 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. PMID: 26727002


  11. 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 letters 2015. PMID: 26529392


  12. 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. Immunity & ageing : I & A 2015. PMID: 26157468


  13. 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. Myelodysplastic syndromes, version 2.2015. Journal of the National Comprehensive Cancer Network : JNCCN 2015. PMID: 25736003


  14. 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. Volume 15 of Issue 6. Clinical lymphoma, myeloma & leukemia 2015. PMID: 25776193


  15. 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 2014. PMID: 25363772


  16. 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. Volume 50 of Issue 1. Bone marrow transplantation 2014. PMID: 25243620


  17. 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. Journal of geriatric oncology 2014. PMID: 24894413


  18. 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 therapy 2013. PMID: 23759700


  19. 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. PMID: 23667469


  20. 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. Molecular therapy : the journal of the American Society of Gene Therapy 2012. PMID: 22871662


  21. 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. Molecular therapy. Nucleic acids 2012. PMID: 23344176


  22. Alhashem YN, Vinjamur DS, Basu M, Klingmüller U, Gaensler KM, Lloyd JA. Transcription factors KLF1 and KLF2 positively regulate embryonic and fetal beta-globin genes through direct promoter binding. The Journal of biological chemistry 2011. PMID: 21610079


  23. Hacke K, Falahati R, Flebbe-Rehwaldt L, Kasahara N, Gaensler KM. Suppression of HLA expression by lentivirus-mediated gene transfer of siRNA cassettes and in vivo chemoselection to enhance hematopoietic stem cell transplantation. Immunologic research 2009. PMID: 19048410


  24. Damon L, Damon LE, Gaensler K, Kaplan L, Martin T, Rubenstein J, Linker C. Impact of intensive PBSC mobilization therapy on outcomes following auto-SCT for non-Hodgkin's lymphoma. Bone marrow transplantation 2008. PMID: 18679366


  25. Keys JR, Tallack MR, Zhan Y, Papathanasiou P, Goodnow CC, Gaensler KM, Crossley M, Dekker J, Perkins AC. A mechanism for Ikaros regulation of human globin gene switching. British journal of haematology 2008. PMID: 18318763


  26. Rupon JW, Wang SZ, Gaensler K, Lloyd J, Ginder GD. Methyl binding domain protein 2 mediates gamma-globin gene silencing in adult human betaYAC transgenic mice. Proceedings of the National Academy of Sciences of the United States of America 2006. PMID: 16608912


  27. Basu P, Morris PE, Haar JL, Wani MA, Lingrel JB, Gaensler KM, Lloyd JA. KLF2 is essential for primitive erythropoiesis and regulates the human and murine embryonic beta-like globin genes in vivo. Blood 2005. PMID: 15947087


  28. Lipshutz GS, Titre D, Brindle M, Bisconte AR, Contag CH, Gaensler KM. Comparison of gene expression after intraperitoneal delivery of AAV2 or AAV5 in utero. Molecular therapy : the journal of the American Society of Gene Therapy 2003. PMID: 12842432


  29. Gaensler KM, Zhang Z, Lin C, Yang S, Hardt K, Flebbe-Rehwaldt L. Sequences in the (A)gamma-delta intergenic region are not required for stage-specific regulation of the human beta-globin gene locus. Proceedings of the National Academy of Sciences of the United States of America 2003. PMID: 12629213


  30. Lipshutz GS, Gruber CA, Hardy J, Contag CH, Gaensler KM. In utero delivery of adeno-associated viral vectors: intraperitoneal gene transfer produces long-term expression. Molecular therapy : the journal of the American Society of Gene Therapy 2001. PMID: 11273769


  31. Lipshutz GS, Flebbe-Rehwaldt L, Gaensler KM. Reexpression following readministration of an adenoviral vector in adult mice after initial in utero adenoviral administration. Molecular therapy : the journal of the American Society of Gene Therapy 2000. PMID: 11020353


  32. May C, Rivella S, Callegari J, Heller G, Gaensler KM, Luzzatto L, Sadelain M. Therapeutic haemoglobin synthesis in beta-thalassaemic mice expressing lentivirus-encoded human beta-globin. Nature 2000. PMID: 10894546


  33. Gaensler KM, Tu G, Bruch S, Liggitt D, Lipshutz GS, Metkus A, Harrison M, Heath TD, Debs RJ. Fetal gene transfer by transuterine injection of cationic liposome-DNA complexes. Nature biotechnology 1999. PMID: 10585716


  34. Lipshutz GS, Sarkar R, Flebbe-Rehwaldt L, Kazazian H, Gaensler KM. Short-term correction of factor VIII deficiency in a murine model of hemophilia A after delivery of adenovirus murine factor VIII in utero. Proceedings of the National Academy of Sciences of the United States of America 1999. PMID: 10557319


  35. Lipshutz GS, Flebbe-Rehwaldt L, Gaensler KM. Adenovirus-mediated gene transfer to the peritoneum and hepatic parenchyma of fetal mice in utero. Surgery 1999. PMID: 10455880


  36. Lipshutz GS, Flebbe-Rehwaldt L, Gaensler KM. Adenovirus-mediated gene transfer in the midgestation fetal mouse. The Journal of surgical research 1999. PMID: 10357912


  37. Chang JC, Lu R, Lin C, Xu SM, Kan YW, Porcu S, Carlson E, Kitamura M, Yang S, Flebbe-Rehwaldt L, Gaensler KM. Transgenic knockout mice exclusively expressing human hemoglobin S after transfer of a 240-kb betas-globin yeast artificial chromosome: A mouse model of sickle cell anemia. Proceedings of the National Academy of Sciences of the United States of America 1998. PMID: 9843985


  38. Porcu S, Kitamura M, Witkowska E, Zhang Z, Mutero A, Lin C, Chang J, Gaensler KM. The human beta globin locus introduced by YAC transfer exhibits a specific and reproducible pattern of developmental regulation in transgenic mice. Blood 1997. PMID: 9373272


  39. Perkins AC, Gaensler KM, Orkin SH. Silencing of human fetal globin expression is impaired in the absence of the adult beta-globin gene activator protein EKLF. Proceedings of the National Academy of Sciences of the United States of America 1996. PMID: 8901569


  40. Liu Y, Liggitt D, Zhong W, Tu G, Gaensler K, Debs R. Cationic liposome-mediated intravenous gene delivery. The Journal of biological chemistry 1995. PMID: 7559609


  41. Gaensler KM, Kitamura M, Kan YW. Germ-line transmission and developmental regulation of a 150-kb yeast artificial chromosome containing the human beta-globin locus in transgenic mice. Proceedings of the National Academy of Sciences of the United States of America 1993. PMID: 8248258


  42. Stribling R, Brunette E, Liggitt D, Gaensler K, Debs R. Aerosol gene delivery in vivo. Proceedings of the National Academy of Sciences of the United States of America 1992. PMID: 1454808


  43. Debs R, Pian M, Gaensler K, Clements J, Friend DS, Dobbs L. Prolonged transgene expression in rodent lung cells. American journal of respiratory cell and molecular biology 1992. PMID: 1327013


  44. Gaensler KM, Burmeister M, Brownstein BH, Taillon-Miller P, Myers RM. Physical mapping of yeast artificial chromosomes containing sequences from the human beta-globin gene region. Genomics 1991. PMID: 1916829


  45. Myers RM, Cowie A, Stuve L, Hartzog G, Gaensler K. Genetic and biochemical analysis of the mouse beta-major globin promoter. Progress in clinical and biological research 1989. PMID: 2594802