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)
Jamie Y. Story, BS
Education: Graduate Student, Emory University; BS, DePauw University, Greencastle, IN
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
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.
Raikar SS, Scarborough JD, Sabnis H, Bergsagel J, Wu D, Cooper TM, Keller FG, Wood BL, Bunting ST. (2016). Early T-cell precursor acute lymphoblastic leukemia in an infant with an NRAS Q61R mutation and clinical features of juvenile myelomonocytic leukemia. Pediatric Blood & Cancer, 63(9), 1667-70. PMID: 27145535
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).
Hyundai Hope on Wheels Young Investigator Grant - 9/21/2017-6/30/2020
Novel Chimeric Antigen Receptors for the Treatment of T-cell Malignancies
Goal: To develop unique chimeric antigen receptors using variable lymphocyte receptors to target T-cell malignancies.
Aflac Pilot Grant - 9/1/2018-8/31/2020
Microfluidic platform to deliver mRNA knockout reagents for T-cell malignancy-directed CAR T-cell manufacturing
Goal: Utilize innovative microfluidic mechanotransfection as a means to deliver CRISPR/Cas9 editing molecules for T-cell malignancy-directed CAR T-cell engineering.