Bio

Bio


Sneha Ramakrishna, M.D., is an Instructor of Pediatrics in the Division of Hematology and Oncology. Dr. Ramakrishna obtained her B. A. from the University of Chicago and her M.D. from the Cleveland Clinic Lerner College of Medicine at Case Western Reserve University. She completed her residency training in Pediatrics at the Children’s Hospital of Philadelphia and her fellowship in Pediatric Hematology/Oncology at the Johns Hopkins/National Cancer Institute combined program. Her research focuses on identifying mechanisms of relapse following chimeric antigen receptor (CAR) T cell therapies and optimizing both CAR design and tumor sensitivity to improve long-term success of CAR T cell therapies.

Clinical Focus


  • Hematology/Oncology

Academic Appointments


Professional Education


  • Residency:Children's Hospital of Philadelphia Pediatric Residency (2015) PA
  • Fellowship:Johns Hopkins and National Cancer Institute Ped Hematology and Oncology Training (2018) MD
  • Board Certification: Pediatrics, American Board of Pediatrics (2015)
  • Medical Education:Case Western Reserve School of Medicine (2012) OH

Research & Scholarship

Clinical Trials


  • Phase I CD19/CD22 Chimeric Antigen Receptor T Cells in Peds Recurrent/Refractory B Cell Malignancies Recruiting

    This phase I trial studies the best dose and side effects of CD19/CD22 chimeric antigen receptor (CAR) T cells when given together with chemotherapy, and to see how well they work in treating children or young adults with CD19 positive B acute lymphoblastic leukemia that has come back or does not respond to treatment. A CAR is a genetically-engineered receptor made so that immune cells (T cells) can attack cancer cells by recognizing and responding to the CD19/CD22 proteins. These proteins are commonly found on B acute lymphoblastic leukemia. Drugs used in chemotherapy, such as fludarabine phosphate and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving CD19/CD22-CAR T cells and chemotherapy may work better in treating children or young adults with B acute lymphoblastic leukemia.

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Publications

All Publications


  • Modulation of Target Antigen Density Improves CAR T Cell Functionality and Persistence. Clinical cancer research : an official journal of the American Association for Cancer Research Ramakrishna, S., Highfill, S. L., Walsh, Z., Nguyen, S. M., Lei, H., Shern, J. F., Qin, H., Kraft, I. L., Stetler-Stevenson, M., Yuan, C. M., Hwang, J. D., Feng, Y., Zhu, Z., Dimitrov, D., Shah, N. N., Fry, T. 2019

    Abstract

    Chimeric antigen receptor T cell (CART) therapy targeting CD22 induces remission in 70% of patients with relapsed/refractory acute lymphoblastic leukemia (ALL). However, the majority of post-CD22 CART remissions are short and associated with reduction in CD22 expression. We evaluate the implications of low antigen density on the activity of CD22 CART and propose mechanisms to overcome antigen escape.Using ALL cell lines with variable CD22 expression, we evaluate the cytokine profile, cytotoxicity, and in vivo CART functionality in the setting of low CD22 expression. We develop a high-affinity CD22 CAR as an approach to improve CAR sensitivity. We also assess Bryostatin1, a therapeutically relevant agent, to upregulate CD22 and improve CAR functionality.We demonstrate that low CD22 expression negatively impacts in vitro and in vivo CD22 CART functionality and impairs in vivo CART persistence. Moreover, low antigen expression on leukemic cells increases naïve phenotype of persisting CART. Increasing CAR affinity does not improve response to low-antigen leukemia. Bryostatin1 upregulates CD22 on leukemia and lymphoma cell lines for 1 week following single-dose exposure, improves CART functionality and in vivo persistence. While Bryostatin1 attenuates IFN-gamma production by CART, overall in vitro and in vivo CART cytotoxicity is not adversely affected. Finally, administration of Bryostain1 with CD22 CAR results in longer duration of in vivo response.We demonstrate that target antigen modulation is a promising strategy to improve CD22 CAR efficacy and remission durability in patients with leukemia and lymphoma.

    View details for DOI 10.1158/1078-0432.CCR-18-3784

    View details for PubMedID 31110075

  • Preclinical Development of Bivalent Chimeric Antigen Receptors Targeting Both CD19 and CD22 MOLECULAR THERAPY-ONCOLYTICS Qin, H., Ramakrishna, S., Nguyen, S., Fountaine, T. J., Ponduri, A., Stetler-Stevenson, M., Yuan, C. M., Haso, W., Shern, J. F., Shah, N. N., Fry, T. J. 2018; 11: 127–37

    Abstract

    Despite high remission rates following CAR-T cell therapy in B-ALL, relapse due to loss of the targeted antigen is increasingly recognized as a mechanism of immune escape. We hypothesized that simultaneous targeting of CD19 and CD22 may reduce the likelihood of antigen loss, thus improving sustained remission rates. A systematic approach to the generation of CAR constructs incorporating two target-binding domains led to several novel CD19/CD22 bivalent CAR constructs. Importantly, we demonstrate the challenges associated with the construction of a bivalent CAR format that preserves bifunctionality against both CD19 and CD22. Using the most active bivalent CAR constructs, we found similar transduction efficiency compared to that of either CD19 or CD22 single CARs alone. When expressed on human T cells, the optimized CD19/CD22 CAR construct induced comparable interferon γ and interleukin-2 in vitro compared to single CARs against dual-antigen-expressing as well as single-antigen-expressing cell lines. Finally, the T cells expressing CD19/CD22 CAR eradicated ALL cell line xenografts and patient-derived xenografts (PDX), including a PDX generated from a patient with CD19- relapse following CD19-directed CAR therapy. The CD19/CD22 bivalent CAR provides an opportunity to test whether simultaneous targeting may reduce risk of antigen loss.

    View details for DOI 10.1016/j.omto.2018.10.006

    View details for Web of Science ID 000454075900012

    View details for PubMedID 30581986

    View details for PubMedCentralID PMC6300726

  • CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy. Nature medicine Fry, T. J., Shah, N. N., Orentas, R. J., Stetler-Stevenson, M., Yuan, C. M., Ramakrishna, S., Wolters, P., Martin, S., Delbrook, C., Yates, B., Shalabi, H., Fountaine, T. J., Shern, J. F., Majzner, R. G., Stroncek, D. F., Sabatino, M., Feng, Y., Dimitrov, D. S., Zhang, L., Nguyen, S., Qin, H., Dropulic, B., Lee, D. W., Mackall, C. L. 2017

    Abstract

    Chimeric antigen receptor (CAR) T cells targeting CD19 mediate potent effects in relapsed and/or refractory pre-B cell acute lymphoblastic leukemia (B-ALL), but antigen loss is a frequent cause of resistance to CD19-targeted immunotherapy. CD22 is also expressed in most cases of B-ALL and is usually retained following CD19 loss. We report results from a phase 1 trial testing a new CD22-targeted CAR (CD22-CAR) in 21 children and adults, including 17 who were previously treated with CD19-directed immunotherapy. Dose-dependent antileukemic activity was observed, with complete remission obtained in 73% (11/15) of patients receiving ≥1 × 106 CD22-CAR T cells per kg body weight, including 5 of 5 patients with CD19dim or CD19- B-ALL. Median remission duration was 6 months. Relapses were associated with diminished CD22 site density that likely permitted CD22+ cell escape from killing by CD22-CAR T cells. These results are the first to establish the clinical activity of a CD22-CAR in B-ALL, including leukemia resistant to anti-CD19 immunotherapy, demonstrating potency against B-ALL comparable to that of CD19-CAR at biologically active doses. Our results also highlight the critical role played by antigen density in regulating CAR function.

    View details for PubMedID 29155426

  • Reduction of MDSCs with All-trans Retinoic Acid Improves CAR Therapy Efficacy for Sarcomas CANCER IMMUNOLOGY RESEARCH Long, A. H., Highfill, S. L., Cui, Y., Smith, J. P., Walker, A. J., Ramakrishna, S., El-Etriby, R., Galli, S., Tsokos, M. G., Orentas, R. J., Mackall, C. L. 2016; 4 (10): 869-880

    Abstract

    Genetically engineered T cells expressing CD19-specific chimeric antigen receptors (CAR) have shown impressive activity against B-cell malignancies, and preliminary results suggest that T cells expressing a first-generation disialoganglioside (GD2)-specific CAR can also provide clinical benefit in patients with neuroblastoma. We sought to assess the potential of GD2-CAR therapies to treat pediatric sarcomas. We observed that 18 of 18 (100%) of osteosarcomas, 2 of 15 (13%) of rhabdomyosarcomas, and 7 of 35 (20%) of Ewing sarcomas expressed GD2. T cells engineered to express a third-generation GD2-CAR incorporating the 14g2a-scFv with the CD28, OX40, and CD3ζ signaling domains (14g2a.CD28.OX40.ζ) mediated efficient and comparable lysis of both GD2(+) sarcoma and neuroblastoma cell lines in vitro However, in xenograft models, GD2-CAR T cells had no antitumor effect against GD2(+) sarcoma, despite effectively controlling GD2(+) neuroblastoma. We observed that pediatric sarcoma xenografts, but not neuroblastoma xenografts, induced large populations of monocytic and granulocytic murine myeloid-derived suppressor cells (MDSC) that inhibited human CAR T-cell responses in vitro Treatment of sarcoma-bearing mice with all-trans retinoic acid (ATRA) largely eradicated monocytic MDSCs and diminished the suppressive capacity of granulocytic MDSCs. Combined therapy using GD2-CAR T cells plus ATRA significantly improved antitumor efficacy against sarcoma xenografts. We conclude that retinoids provide a clinically accessible class of agents capable of diminishing the suppressive effects of MDSCs, and that co-administration of retinoids may enhance the efficacy of CAR therapies targeting solid tumors. Cancer Immunol Res; 4(10); 869-80. ©2016 AACR.

    View details for DOI 10.1158/2326-6066.CIR-15-0230

    View details for Web of Science ID 000385632900007

    View details for PubMedID 27549124

    View details for PubMedCentralID PMC5050151