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Crystal Mackall

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Crystal L. Mackall (born August 21, 1960) is an American physician and immunologist. She is currently the Ernest and Amelia Gallo Family Professor of Pediatrics and Medicine at Stanford University.[1][2] She is the founding director of the Stanford Center for Cancer Cell Therapy.

Crystal Mackall
Mackall at the National Cancer Institute in 2002
Born
Crystal L. Mackall
Alma materUniversity of Akron
Northeast Ohio Medical University
AwardsNational Institutes of Health Director's Award
National Cancer Institute Director's Award
Scientific career
FieldsImmunotherapy
Chimeric antigen receptors
Pediatric oncology
T cell homeostasis[1]
InstitutionsStanford University
National Cancer Institute
National Institutes of Health
Websiteprofiles.stanford.edu/crystal-mackall

Education and early career

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Mackall grew up in East Palestine, Ohio in a working-class family; her father was a steelworker. She received her medical training through a six-year BS/MD program, earning her bachelor's degree at the University of Akron and graduated summa cum laude.[3] She completed her medical education at Northeast Ohio Medical University, earning her Doctor of Medicine in 1984. She was a member of the Alpha Omega Alpha honour society. Mackall completed an internal medicine and pediatrics Residency at Cleveland Clinic Akron General and Children's Hospital of Akron in 1988.[3] In 1989, Mackall joined the National Cancer Institute as a fellow in pediatric oncology, where she began to focus on immunotherapy for cancer.[4][5]  She remained at National Institutes of Health until 2016, eventually serving as the Chief of the Pediatric Oncology Branch.[6]  She moved to the Stanford University School of Medicine in 2016.[6]  She is Board Certified in Internal Medicine, Pediatrics, and Pediatric Hematology/Oncology.[7][8]

Research

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Mackall has pioneered cancer immunotherapies with a major focus on children's cancers. Her early research defined the effects of traditional cancer therapies on the immune system, where she identified the role of the thymus in human T cell regeneration and discovered that Interleukin-7 (IL-7) is the main regulator of T cell homeostasis in humans.[8][9] Her group was among the first to demonstrate impressive activity of CD19 chimeric antigen receptor (CAR T cells) therapies for childhood leukemia and also developed a CAR targeting CD22 that is active in this disease and has received Breakthrough Therapy Designation from the US FDA for treatment of CAR19 refractory B-ALL.[10][11] The CD22-CAR developed by Mackall's team is also active in large B cell lymphoma[12] and has received Breakthrough Therapy Designation from the US FDA for this indication. Working with the Monje lab at Stanford, Mackall developed a GD2-CAR that showed activity in preclinical models of diffuse midline glioma, which are lethal brain tumor occurring primarily in children and young adults,[13] and her group demonstrated that intracerebroventricular delivery of CAR T cells is more potent for treatment of brain tumors in mice than intravenous delivery.[14] Mackall and Monje are leading a clinical trial of GD2-CAR for diffuse midline gliomas, given intravenously and intracerebroventricularly, that has shown clinical activity.[15]

Mackall has elucidated fundamental biology related to T cells, with a focus on T cell exhaustion, demonstrating that cJUN overexpression prevents T cell exhaustion[16] and this work led to the launch of Lyell Immunopharma[17] which is testing this approach in clinical trials. Her group demonstrated that T cell exhaustion can be reversed by transient T cell rest[18] and demonstrated that dasatinib,[19] a commonly prescribed oral drug, could be used to rest human T cells. Mackall and Freitas discovered a role for the mediator kinase modules in regulating T cell effector differentiation and demonstrated that MED12 knockout increased the potency of human T cells in preclinical models.[20] Mackall has led clinical trials of cancer vaccines,[21][22][23] launched the first clinical trial of recombinant human interleukin-7,[24][25] led studies of immune checkpoint inhibitors in pediatric cancers[26][27] and studied a role for bone marrow transplants in pediatric solid tumors.[28][29] In 2018 Mackall was awarded $11.9 million from the California Institute of Regenerative Medicine to lead a clinical trial using genetically modified T cells engineered to recognize CD19 or CD22 proteins expressed on leukemia or lymphoma.[30] The trial was conducted at the Stanford Center for Cancer Cell Therapy, which modified the chimeric antigen receptor T cell (CAR-T) to identify B-cell prolymphocytic leukemia and B-cell lymphoma.[30][31] In 2022, Mackall was awarded $11.9 million from the California Institute of Regenerative Medicine to lead a clinical trial using T cells engineered to express GD2-CAR T cells for treatment of diffuse midline gliomas.[32]

Mackall holds a number of patents relating to peptides, antigen receptors and T cell fitness enhancements. She has served on the editorial boards of several cancer journals, including Cancer Today.

Awards and honors

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Personal life

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She identifies as LGBT and is married to Catherine L. Salem MD. The two have two sons, Theo Salem-Mackall and Zachary Salem-Mackall.[42]

References

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  1. ^ a b Crystal Mackall publications indexed by Google Scholar  
  2. ^ Lee, Daniel W; Kochenderfer, James N; Stetler-Stevenson, Maryalice; Cui, Yongzhi K; Delbrook, Cindy; Feldman, Steven A; Fry, Terry J; Orentas, Rimas; Sabatino, Marianna; Shah, Nirali N; Steinberg, Seth M; Stroncek, Dave; Tschernia, Nick; Yuan, Constance; Zhang, Hua; Zhang, Ling; Rosenberg, Steven A; Wayne, Alan S; Mackall, Crystal L (2015). "T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial". The Lancet. 385 (9967): 517–528. doi:10.1016/S0140-6736(14)61403-3. ISSN 0140-6736. PMC 7065359. PMID 25319501.  
  3. ^ a b "Crystal L. Mackall, MD". aacr.org. Archived from the original on 2019-06-17. Retrieved 2019-06-17.
  4. ^ "Crystal L. Mackall, MD". aacr.org. Archived from the original on 2019-06-17. Retrieved 2019-06-17. [verification needed]
  5. ^ "Crystal Mackall". stanfordhealthcare.org. Archived from the original on 2019-06-17. Retrieved 2019-06-17. [verification needed]
  6. ^ a b "Crystal Mackall, MD". parkerici.org. Parker Institute for Cancer Immunotherapy. Retrieved 2019-06-17. [verification needed]
  7. ^ "Crystal Mackall". stanfordhealthcare.org. Archived from the original on 2019-06-17. Retrieved 2019-06-17.
  8. ^ a b "Crystal Mackall, MD". parkerici.org. Parker Institute for Cancer Immunotherapy. Retrieved 2019-06-17.
  9. ^ "Immunotherapy Expert Crystal Mackall, MD, Joins Stanford Medicine Faculty - The ASCO Post". ascopost.com. Retrieved 2019-06-17.
  10. ^ Fry, Terry J; Shah, Nirali N; Orentas, Rimas J; Stetler-Stevenson, Maryalice; Yuan, Constance M; Ramakrishna, Sneha; Wolters, Pamela; Martin, Staci; Delbrook, Cindy (2018). "CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy". Nature Medicine. 24 (1): 20–28. doi:10.1038/nm.4441. ISSN 1078-8956. PMC 5774642. PMID 29155426.
  11. ^ "FDA grants breakthrough therapy designation for new CAR T-cell therapy for B-cell acute lymphoblastic leukemia". National Cancer Institute at the National Institutes of Health. September 10, 2019.
  12. ^ Baird, John H.; Frank, Matthew J.; Craig, Juliana; Patel, Shabnum; Spiegel, Jay Y.; Sahaf, Bita; Oak, Jean S.; Younes, Sheren F.; Ozawa, Michael G.; Yang, Eric; Natkunam, Yasodha; Tamaresis, John; Ehlinger, Zachary; Reynolds, Warren D.; Arai, Sally (2021-04-29). "CD22-directed CAR T-cell therapy induces complete remissions in CD19-directed CAR-refractory large B-cell lymphoma". Blood. 137 (17): 2321–2325. doi:10.1182/blood.2020009432. ISSN 1528-0020. PMC 8085484. PMID 33512414.
  13. ^ Mount, Christopher W.; Majzner, Robbie G.; Sundaresh, Shree; Arnold, Evan P.; Kadapakkam, Meena; Haile, Samuel; Labanieh, Louai; Hulleman, Esther; Woo, Pamelyn J.; Rietberg, Skyler P.; Vogel, Hannes; Monje, Michelle; Mackall, Crystal L. (May 2018). "Potent antitumor efficacy of anti-GD2 CAR T cells in H3-K27M+ diffuse midline gliomas". Nature Medicine. 24 (5): 572–579. doi:10.1038/s41591-018-0006-x. ISSN 1546-170X. PMC 6214371. PMID 29662203.
  14. ^ Theruvath, Johanna; Sotillo, Elena; Mount, Christopher W.; Graef, Claus Moritz; Delaidelli, Alberto; Heitzeneder, Sabine; Labanieh, Louai; Dhingra, Shaurya; Leruste, Amaury; Majzner, Robbie G.; Xu, Peng; Mueller, Sabine; Yecies, Derek W.; Finetti, Martina A.; Williamson, Daniel (May 2020). "Locoregionally administered B7-H3-targeted CAR T cells for treatment of atypical teratoid/rhabdoid tumors". Nature Medicine. 26 (5): 712–719. doi:10.1038/s41591-020-0821-8. ISSN 1546-170X. PMC 7992505. PMID 32341579.
  15. ^ Majzner, Robbie G.; Ramakrishna, Sneha; Yeom, Kristen W.; Patel, Shabnum; Chinnasamy, Harshini; Schultz, Liora M.; Richards, Rebecca M.; Jiang, Li; Barsan, Valentin; Mancusi, Rebecca; Geraghty, Anna C.; Good, Zinaida; Mochizuki, Aaron Y.; Gillespie, Shawn M.; Toland, Angus Martin Shaw (March 2022). "GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas". Nature. 603 (7903): 934–941. Bibcode:2022Natur.603..934M. doi:10.1038/s41586-022-04489-4. ISSN 1476-4687. PMC 8967714. PMID 35130560.
  16. ^ Lynn, Rachel C.; Weber, Evan W.; Sotillo, Elena; Gennert, David; Xu, Peng; Good, Zinaida; Anbunathan, Hima; Lattin, John; Jones, Robert; Tieu, Victor; Nagaraja, Surya; Granja, Jeffrey; de Bourcy, Charles F. A.; Majzner, Robbie; Satpathy, Ansuman T. (December 2019). "c-Jun overexpression in CAR T cells induces exhaustion resistance". Nature. 576 (7786): 293–300. Bibcode:2019Natur.576..293L. doi:10.1038/s41586-019-1805-z. ISSN 1476-4687. PMC 6944329. PMID 31802004.
  17. ^ "Pioneering Transformative T-Cell Therapies". Lyell. Retrieved 2022-12-30.
  18. ^ Weber, Evan W.; Parker, Kevin R.; Sotillo, Elena; Lynn, Rachel C.; Anbunathan, Hima; Lattin, John; Good, Zinaida; Belk, Julia A.; Daniel, Bence; Klysz, Dorota; Malipatlolla, Meena; Xu, Peng; Bashti, Malek; Heitzeneder, Sabine; Labanieh, Louai (2021-04-02). "Transient rest restores functionality in exhausted CAR-T cells through epigenetic remodeling". Science. 372 (6537): eaba1786. doi:10.1126/science.aba1786. ISSN 1095-9203. PMC 8049103. PMID 33795428.
  19. ^ Weber, Evan W.; Lynn, Rachel C.; Sotillo, Elena; Lattin, John; Xu, Peng; Mackall, Crystal L. (2019-03-12). "Pharmacologic control of CAR-T cell function using dasatinib". Blood Advances. 3 (5): 711–717. doi:10.1182/bloodadvances.2018028720. ISSN 2473-9537. PMC 6418502. PMID 30814055.
  20. ^ Freitas, Katherine A.; Belk, Julia A.; Sotillo, Elena; Quinn, Patrick J.; Ramello, Maria C.; Malipatlolla, Meena; Daniel, Bence; Sandor, Katalin; Klysz, Dorota; Bjelajac, Jeremy; Xu, Peng; Burdsall, Kylie A.; Tieu, Victor; Duong, Vandon T.; Donovan, Micah G. (2022-11-11). "Enhanced T cell effector activity by targeting the Mediator kinase module". Science. 378 (6620): eabn5647. doi:10.1126/science.abn5647. ISSN 1095-9203. PMC 10335827. PMID 36356142. S2CID 253458258.
  21. ^ Zhang, Hua; Chua, Kevin S.; Guimond, Martin; Kapoor, Veena; Brown, Margaret V.; Fleisher, Thomas A.; Long, Lauren M.; Bernstein, Donna; Hill, Brenna J.; Douek, Daniel C.; Berzofsky, Jay A.; Carter, Charles S.; Read, E. J.; Helman, Lee J.; Mackall, Crystal L. (November 2005). "Lymphopenia and interleukin-2 therapy alter homeostasis of CD4+CD25+ regulatory T cells". Nature Medicine. 11 (11): 1238–1243. doi:10.1038/nm1312. ISSN 1078-8956. PMID 16227988. S2CID 24773329.
  22. ^ Mackall, Crystal L.; Rhee, Eunice H.; Read, Elizabeth J.; Khuu, Hanh M.; Leitman, Susan F.; Bernstein, Donna; Tesso, Merertu; Long, Lauren M.; Grindler, David; Merino, Margret; Kopp, William; Tsokos, Maria; Berzofsky, Jay A.; Helman, Lee J. (2008-08-01). "A pilot study of consolidative immunotherapy in patients with high-risk pediatric sarcomas". Clinical Cancer Research. 14 (15): 4850–4858. doi:10.1158/1078-0432.CCR-07-4065. ISSN 1078-0432. PMC 2497450. PMID 18676758.
  23. ^ Merchant, Melinda S.; Bernstein, Donna; Amoako, Martha; Baird, Kristin; Fleisher, Thomas A.; Morre, Michel; Steinberg, Seth M.; Sabatino, Marianna; Stroncek, Dave F.; Venkatasan, Aradhana M.; Wood, Bradford J.; Wright, Matthew; Zhang, Hua; Mackall, Crystal L. (2016-07-01). "Adjuvant Immunotherapy to Improve Outcome in High-Risk Pediatric Sarcomas". Clinical Cancer Research. 22 (13): 3182–3191. doi:10.1158/1078-0432.CCR-15-2550. ISSN 1557-3265. PMC 7831150. PMID 26823601.
  24. ^ Sportès, Claude; Babb, Rebecca R.; Krumlauf, Michael C.; Hakim, Frances T.; Steinberg, Seth M.; Chow, Catherine K.; Brown, Margaret R.; Fleisher, Thomas A.; Noel, Pierre; Maric, Irina; Stetler-Stevenson, Maryalice; Engel, Julie; Buffet, Renaud; Morre, Michel; Amato, Robert J. (2010-01-15). "Phase I study of recombinant human interleukin-7 administration in subjects with refractory malignancy". Clinical Cancer Research. 16 (2): 727–735. doi:10.1158/1078-0432.CCR-09-1303. ISSN 1557-3265. PMC 2808195. PMID 20068111.
  25. ^ Sportès, Claude; Hakim, Frances T.; Memon, Sarfraz A.; Zhang, Hua; Chua, Kevin S.; Brown, Margaret R.; Fleisher, Thomas A.; Krumlauf, Michael C.; Babb, Rebecca R.; Chow, Catherine K.; Fry, Terry J.; Engels, Julie; Buffet, Renaud; Morre, Michel; Amato, Robert J. (2008-07-07). "Administration of rhIL-7 in humans increases in vivo TCR repertoire diversity by preferential expansion of naive T cell subsets". The Journal of Experimental Medicine. 205 (7): 1701–1714. doi:10.1084/jem.20071681. ISSN 1540-9538. PMC 2442646. PMID 18573906.
  26. ^ Merchant, Melinda S.; Wright, Matthew; Baird, Kristin; Wexler, Leonard H.; Rodriguez-Galindo, Carlos; Bernstein, Donna; Delbrook, Cindy; Lodish, Maya; Bishop, Rachel; Wolchok, Jedd D.; Streicher, Howard; Mackall, Crystal L. (2016-03-15). "Phase I Clinical Trial of Ipilimumab in Pediatric Patients with Advanced Solid Tumors". Clinical Cancer Research. 22 (6): 1364–1370. doi:10.1158/1078-0432.CCR-15-0491. ISSN 1557-3265. PMC 5027962. PMID 26534966.
  27. ^ Davis, Kara L.; Fox, Elizabeth; Merchant, Melinda S.; Reid, Joel M.; Kudgus, Rachel A.; Liu, Xiaowei; Minard, Charles G.; Voss, Stephan; Berg, Stacey L.; Weigel, Brenda J.; Mackall, Crystal L. (April 2020). "Nivolumab in children and young adults with relapsed or refractory solid tumours or lymphoma (ADVL1412): a multicentre, open-label, single-arm, phase 1-2 trial". The Lancet. Oncology. 21 (4): 541–550. doi:10.1016/S1470-2045(20)30023-1. ISSN 1474-5488. PMC 7255545. PMID 32192573.
  28. ^ Baird, Kristin; Fry, Terry J.; Steinberg, Seth M.; Bishop, Michael R.; Fowler, Daniel H.; Delbrook, Cynthia P.; Humphrey, Jennifer L.; Rager, Alison; Richards, Kelly; Wayne, Alan S.; Mackall, Crystal L. (May 2012). "Reduced-intensity allogeneic stem cell transplantation in children and young adults with ultrahigh-risk pediatric sarcomas". Biology of Blood and Marrow Transplantation. 18 (5): 698–707. doi:10.1016/j.bbmt.2011.08.020. ISSN 1523-6536. PMC 3262116. PMID 21896345.
  29. ^ Shah, Nirali N.; Baird, Kristin; Delbrook, Cynthia P.; Fleisher, Thomas A.; Kohler, Mark E.; Rampertaap, Shakuntala; Lemberg, Kimberly; Hurley, Carolyn K.; Kleiner, David E.; Merchant, Melinda S.; Pittaluga, Stefania; Sabatino, Marianna; Stroncek, David F.; Wayne, Alan S.; Zhang, Hua (2015-01-29). "Acute GVHD in patients receiving IL-15/4-1BBL activated NK cells following T-cell-depleted stem cell transplantation". Blood. 125 (5): 784–792. doi:10.1182/blood-2014-07-592881. ISSN 1528-0020. PMC 4311226. PMID 25452614.
  30. ^ a b "Mackall awarded $11.9 million for anti-leukemia clinical trial". med.stanford.edu. 20 November 2017. Retrieved 2019-06-17.
  31. ^ Spiegel, Jay Y.; Patel, Shabnum; Muffly, Lori; Hossain, Nasheed M.; Oak, Jean; Baird, John H.; Frank, Matthew J.; Shiraz, Parveen; Sahaf, Bita; Craig, Juliana; Iglesias, Maria; Younes, Sheren; Natkunam, Yasodha; Ozawa, Michael G.; Yang, Eric (August 2021). "CAR T cells with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B cell malignancies: a phase 1 trial". Nature Medicine. 27 (8): 1419–1431. doi:10.1038/s41591-021-01436-0. ISSN 1546-170X. PMC 8363505. PMID 34312556.
  32. ^ cirm_2.0 (2022-12-30). "Phase 1 Clinical Trial of Autologous GD2 Chimeric Antigen Receptor T Cells for Diffuse Intrinsic Pontine Gliomas and Spinal Diffuse Midline Glioma". California's Stem Cell Agency. Retrieved 2022-12-30.{{cite web}}: CS1 maint: numeric names: authors list (link)
  33. ^ "Crystal Mackall's Profile | Stanford Profiles". profiles.stanford.edu. Retrieved 2020-10-18.
  34. ^ "Lila and Murray Gruber Memorial Cancer Research Award and Lectureship". www.aad.org. Retrieved 2020-10-18.
  35. ^ "Ludwig Cancer Research". Retrieved 2022-12-30.
  36. ^ "AACR to Recognize the St. Baldrick's Foundation-Stand Up To Cancer Pediatric Cancer Dream Team with 2021 Team Science Award". American Association for Cancer Research (AACR). Retrieved 2022-12-30.
  37. ^ "SITC Smalley Award 2021 Recipient | Richard V. Smalley, MD Memorial Award". www.sitcancer.org. Retrieved 2022-12-30.
  38. ^ "Dr. Crystal L. Mackall Named Pediatric Oncology Award Recipient for Research in Immuno-Oncology". ASCO Daily News. 2021. doi:10.1200/ADN.21.200537. S2CID 243534420. Retrieved 2022-12-30.
  39. ^ "AACR Announces Fellows of the AACR Academy Class of 2022". American Association for Cancer Research (AACR). Retrieved 2022-12-30.
  40. ^ Saunders, Cindy (2022-08-30). "SFA Honors Crystal L. Mackall with 2022 Nobility in Science Award". Sarcoma Foundation of America. Retrieved 2022-12-30.
  41. ^ "Six professors elected to the National Academy of Medicine". News Center (in Samoan). 20 October 2021. Retrieved 2022-12-30.
  42. ^ "+OUTlist". Stanford Medicine. Retrieved 2020-10-18.
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