Overview
The overall goal of the Raikar laboratory is to develop novel therapeutics for children with blood cancers (leukemia and lymphoma) by utilizing and enhancing the inherent anti-tumor properties of our own immune system. While the survival of pediatric leukemia patients has greatly improved with the intensification of chemotherapy, relapsed disease still accounts for high rate of mortality among childhood cancer patients. Additionally, current chemotherapy regimens can have significant long-term toxicities. Thus, a need exists to develop novel alternative approaches to target relapsed disease with lesser side effects.
In recent years, chimeric antigen receptor (CAR) T-cell immunotherapy for relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) has been a revolutionary breakthrough in pediatric cancer. In this form of therapy, the patient’s own immune cells (T cells) are genetically modified to express receptors called CARs, which enable them to specifically target B cells. While CAR T-cell therapy is extremely successful in targeting B-cell cancers, the same approach has not been successful in targeting T-cell cancers such as T-cell acute lymphoblastic leukemia (T-ALL), which has a higher rate of relapse and is more difficult to cure compared to B-ALL. Dr. Raikar’s research is centered on adapting this novel CAR technology to T-cell disease. Given the lack of a tumor specific antigen in T-cell malignancies, utilizing CAR-based immunotherapy in this disease has been extremely challenging as it can result in (i) fratricide (self-killing) of CAR T cells, (ii) long-standing immunosuppression from T-cell aplasia and (iii) product contamination from accidental transduction of malignant T cells. Dr. Raikar is exploring several different approaches to overcome these challenges, including the use of unique immune cells such as natural killer cells and gamma delta T cells. As an extension of this work, Dr. Raikar is now also exploring the use of cellular therapy in acute myeloid leukemia (AML), a more aggressive form of childhood blood cancer with survival around 60-70%.
Dr. Raikar is also a member of the clinical leukemia/lymphoma team at the Aflac Cancer and Blood Disorders Center at Children’s Healthcare of Atlanta. Through his national involvement with the Children’s Oncology Group (COG), where he serves on the T-ALL and MPAL (mixed phenotype acute leukemia) disease committees, Dr. Raikar also maintains a strong presence in the concept, design and implementation of clinical studies in these high-risk leukemia populations.
- Developing chimeric antigen receptor (CAR) based strategies to target T-cell malignancies
- Utilizing gamma delta T cells in combination with chemotherapeutic agents to target AML and T-ALL
- Utilizing microfluidic mechanotransfection as a means to deliver CRISPR/Cas9 editing molecules for T-cell malignancy-directed CAR T-cell engineering (collaboration with Todd Sulchek, PhD)
- Studying the effects of the obese microenvironment on CAR T-cell function (collaboration with Curtis Henry, PhD)
Navdeep Jhita, MD, Post-Doctoral Fellow
Education: BS, McMaster University; MD, International American University College of Medicine, Post-Doctoral Fellowship, Emory University
Email: navdeep.jhita@emory.edu
Emily Sullivan, BS, Molecular and Systems Pharmacology Graduate Student
Education: BS, University of New Hampshire
Email: emily.sullivan@emory.edu
Kristopher Knight, BS, Molecular and Systems Pharmacology Graduate Student
Education: BS, The University of the West Indies
Email: kristopher.knight@emory.edu
Jamie Y. Story, PhD, MSCR, Graduate Student, Emory University, Medical Writer, SciMentum, Atlanta, GA
Laboratory Publications
Hamilton JAG, Lee MY, Hunter R, Ank RS, Story JY, Talekar G, Sisroe T, Ballak DB, Fedanov A, Porter CC, Eisenmesser EZ, Dinarello CA, Raikar SS, DeGregori J, Henry CJ. (2021). Interleukin-37 Improves T-cell mediated immunity and chimeric antigen receptor T-cell therapy in aged backgrounds. Aging Cell. 20(2):e13309. PMID: 33480151; PMCID: PMC7884049.
Story JY, Zoine JT, Burnham RE, Hamilton JAG, Spencer HT, Doering CB, Raikar SS. (2021). Bortezomib enhances cytotoxicity of ex vivo-expanded gamma delta T cells against acute myeloid leukemia and T-cell acute lymphoblastic leukemia. Cytotherapy. 23(1):12-24. PMID: 33168453.
Fleischer LC, Spencer HT, Raikar SS. (2019) Targeting T cell malignancies using CAR-based immunotherapy: challenges and potential solutions. Journal of Hematology & Oncology. 12(1):141. PMID: 31884955; PMCID: PMC6936092.
Petersen CT, Hassan M, Morris AB, Jeffery J, Lee K, Jagirdar N, Staton AD, Raikar SS, Spencer HT, Sulchek T, Flowers CR, Waller EK. (2018). Improving T-cell expansion and function for adoptive T-cell therapy using ex vivo treatment with PI3Kδ inhibitors and VIP antagonists. Blood Advances, 2(3), 210-223. PMID: 29386194; PMCID: PMC5812323.
Raikar SS, Fleischer LC, Moot R, Fedanov A, Paik NY, Knight KA, Doering CB, Spencer HT. (2018). Development of chimeric antigen receptors targeting T-cell malignancies using two structurally different anti-CD5 antigen binding domains in NK and CRISPR-edited T cell lines. Oncoimmunology, 7(3), e1407898. PMID: 29399409; PMCID: PMC5790337.
Moot R*, Raikar SS*, Fleischer L, Querrey M, Tylawsky DE, Nakahara H, Doering CB, Spencer HT. (2016). Genetic engineering of chimeric antigen receptors using lamprey derived variable lymphocyte receptors. Molecular Therapy – Oncolytics, 3, 16026. PMID: 27933313; PMCID: PMC5142425. (*Co-first authors)
Selected Clinical Publications
Jain J, Weinzierl EP, Saxe D, Bergsagel J, Gotlib J, Reiter A, Raikar SS. (2020). Sustained complete molecular remission with imatinib monotherapy in a child presenting with blast phase FIP1L1-PDGFRA-associated myeloid neoplasm with eosinophilia. HemaSphere. 4(6):e486. PMID: 33196011; PMCID: PMC7655083.
Oberley MJ*, Raikar SS*, Malvar J, Wertheim G, Seif AE, Guinipero T, Sposto R, Rabin KR, Punia JN, Schore RJ, Luca DC, Woods WG, O'Gorman MRG and Orgel E. (2020). Significance of minimal residual disease in pediatric mixed phenotype acute leukemia: a multicenter cohort study. Leukemia. 2020 Feb 14. PMID: 32060402. (*Co-first authors)
Raikar SS, Felker J, Lew G, Patel K, Sidonio RF Jr. (2018). Acquired hypofibrinogenemia before asparaginase exposure during induction therapy for pediatric acute lymphoblastic leukemia: a report of 2 cases and review of the literature. Journal of Pediatric Hematology/Oncology, 40(7), e470-e472. PMID: 29401102.
Raikar SS, Park SI, Leong T, Jaye DL, Keller FG, Horan JT, Woods WG. (2018). Isolated myeloperoxidase expression in pediatric B/myeloid mixed phenotype acute leukemia is linked with better survival. Blood, 131(5), 573-577. PMID: 29223952.
NIH/NCI: 1K08CA248962-01 - 4/1/2020-3/30/2025
Gamma delta T-cell immunotherapy for T-cell acute lymphoblastic leukemia
Goal: To target T-ALL with innate-like cytotoxic gamma delta (γδ) T cells using two different strategies, one utilizing cellular stress modulation to sensitize T-ALL to γδ T-cell killing, and the other through the use of CD5-directed chimeric antigen receptors (CARs).
Role: PI
NIH/NCI: R21CA256605 - 12/10/2020-11/30/2021
Microfluidic platforms to generate 'off-the-shelf' fratricide-resistant CAR T cells for T-cell malignancies
Goal: To test a novel microfluidic platform to create multiple genome edits in T cells, thereby enabling us to develop an effective “off-the-shelf” fratricide-resistant CAR T-cell product for T-cell disease.
Role: MPI