1. Personal Statement

After obtaining my medical degree from Pondicherry University in India, I moved to the United States for my residency in neurology followed by a fellowship in neuro-oncology at the National Institutes of  Health and at Johns Hopkins University leading to a United Council for Neurologic Subspecialty Board certification. y I gained an excellent background in brain tumor patient management, but also saw the lack of really effective therapies. I sought out coursework providing additional training in principles and practice of clinical research to develop my expertise in clinical trial design and development. This work showed me that I want to be involved in the entire range of therapy development, from initial concept through preclinical research, translating to novel and ethical clinical trials.

      My current position as the director of neuro-oncology program at the Providence brain and Spine Institute allows me to focus on translational research. My clinical research foci are immunotherapy for brain tumors and validating novel MRI contrast agents. I have developed two clinical studies that use the unique properties of ferumoxytol, an iron oxide nanoparticle for magnetic resonance imaging (MRI) as a contrast agent to help with response assessment in brain tumors. In addition, I am currently a co-investigator and collaborator on multiple imaging studies using ferumoxytol, as well as therapeutic trials for brain tumor patients. I have presented my clinical and preclinical research at multiple national and international scientific meetings.

      I have focused considerable time and effort over the last three years to improve my preclinical expertise. My preclinical research focus has been on the use of antisense oligonucleotides useful in cancer and enhanced delivery into the brain across the neurovascular unit using non-ablative doses of radiation. My efforts have resulted in multiple publications and a US. Patent application. I am currently working towards the clinical translation of this approach with early phase clinical trials.

1. Neuwelt E, Ambady P, Muldoon L, McConnell H, Doolittle N. Outwitting the Blood-Brain Barrier. Oncology (Williston Park) 2016;30:963, 6-7.
2. Ambady P, Bettegowda C, Holdhoff M. Emerging methods for disease monitoring in malignant gliomas. CNS Oncol. 2013;2(6):511-22. PMCID: 4986516.

B. Positions and Honors

Positions and Employment

2022-current              Director, Neuro-Oncology program, Providence Brain and Spine institute, Portland, OR

2020-2022                  Associate Professor, Department of Neurology, OHSU, Portland, OR

2014-2022                   Assistant Professor, Department of Neurology, OHSU, Portland, OR

2018- 2022                  Clinical director of Neuro-Oncology, OHSU, Portland, OR

Honors

2018                            Best faculty teacher award, Department of Neurology,

2017                            Neurology Department Research Day, Best faculty research award,

2014                            Driskill scholar in translational research

2013                            American Society of Clinical Oncology/American Association of Clinical Research, scholarship assistance to attend workshop on methods in clinical cancer research

2012                            Best resident research project award

2012                            Best resident teacher award

2010                            Robert J. Schwartzman outstanding neurology resident award

Professional Memberships

2015-Current               American society for clinical Oncology

2012-Current               Society for Neuro-Oncology

2009-Current               American Academy of Neurology

2003-Current               Indian Medical Association

C. Contributions to Science

PubMed link for full list of publication is available : https://pubmed.ncbi.nlm.nih.gov/?term=Ambady%20P&sort=date

I. Targeted delivery and use of antisense technology to treat cancer

Although antisense technology has been around for over 15 years , its translation to clinical use is significnatly limited by challenges in targed delivery. We reported the first successful use of a non-ablative dose of ionizing radiation to prime human cancer cells to enhance the uptake of unmodified morpholino oligonucleotide sequences in a tumor bearing animal model (Ambady et al . 2017). In this report, we demonstrate the efficacy of a non-lethal dose of ionizing radiation upregulates physiologic endocytosis to to guide and enhance the intracellular uptake of unmodified antisense morpholino oligonucleotide sequences and to silence MGMT protein expression. A US patent application is pending for these sequences. We used MGMT as the prototype to demonstrate the proof of concept for modulating a cancer-specific protein; this technique can potentially be used to target other proteins. Based on this preliminary evidence we have now developed addition sequences including the anti-PD-L1 morpholinos and have successfully demonstrated silencing of target protein in a brain tumor model. As radiation therapy already is widely used in the management of various cancers, targeted delivery of systemically administered antisense oligonucleotides only to the ‘field of radiation’ will limit potential systemic side effects associated with many cancer therapies. 

1. Ambady P, Wu YJ, Walker JM, Kersch C, Pagel MA, Woltjer RL, et al. Enhancing the cytotoxicity of chemoradiation with radiation-guided delivery of anti-MGMT morpholino oligonucleotides in non-methylated solid tumors. Cancer Gene Ther. 2017;24(8):348-57. PMCID: 5605678.
2. Ambady P, Wu YJ, Kersch CN, Walker JM, Holland S, Muldoon LL, Neuwelt EA. Radiation enhances the delivery of antisense oligonucleotides and improves chemo-radiation efficacy in brain tumor xenografts. Cancer Gene Ther. 2022;29(5):533-42. Epub 20210414. doi: 10.1038/s41417-021-00324-6. PubMed PMID: 33850305; PMCID: PMC9113935.

II. Investigation of ferumoxytol for non-invasive imaging biomarkers for response assessment in the central nervous system: Pseudoprogression is seen in up to 30% of brain tumors after radiation and its incidence is expected to increase with the addition of immunomodulatory therapies such as check point inhibitors. Currently available imaging techniques and response assessment criteria is inadequate in reliably detecting pseudoprogression. As a young investigator, my research focus is on validating imaging techniques for response assessment after radiation and novel immunotherapy. I have designed two investigator initiated clinical trials to evaluate the role of ferumoxytol steady state imaging in early detection and distinguishing true from pseudoprogression in primary and metastatic brain tumors. I expect that the proposed clinical studies and preclinical experiments will generate a number of high-quality publications and provide preliminary data that can help overcome the challenges in non-invasively measuring response to brain tumor therapies.

1. Barajas RF, Jr., Hamilton BE, Schwartz D, McConnell HL, Pettersson DR, Horvath A, et al. Combined Iron Oxide Nanoparticle Ferumoxytol and Gadolinium Contrast Enhanced MRI Defines Glioblastoma Pseudo-progression. Neuro Oncol. 2018.
2. Horvath A, Varallyay CG, Schwartz D, Toth GB, Netto JP, Barajas R, et al. Quantitative comparison of delayed ferumoxytol T1 enhancement with immediate gadoteridol enhancement in high grade gliomas. Magn Reson Med. 2018;80(1):224-30. PMCID: 5876095.
3. Varallyay CG, Toth GB, Fu R, Netto JP, Firkins J, Ambady P, et al. What Does the Boxed Warning Tell Us ? Safe Practice of Using Ferumoxytol as an MRI Contrast Agent. AJNR Am J Neuroradiol. 2017;38(7):1297-302. PMCID: 5509484.
4. Toth GB, Varallyay CG, Horvath A, Bashir MR, Choyke PL, Daldrup-Link HE, et al. Current and potential imaging applications of ferumoxytol for magnetic resonance imaging. Kidney Int. 2017;92(1):47-66. PMCID: 5505659.

III. Role of immunotherapy in primary central nervous system lymphoma. My work as a neuro-oncology fellow at Johns Hopkins Hospital under the mentorship of Dr. Stuart Grossman focused on the use of immunotherapy and the pattern of late relapses in primary central nervous system lymphoma. We demonstrated that there was significant improvement in rates of complete remission as well as overall survival when rituximab, a CD-20 targeted immunoglobulin, was added to high dose methotrexate therapy. We also demonstrated that unlike systemic lymphoma, delayed relapses in primary CNS lymphoma continue to occur even 5 years after complete remission following treatment with high dose methotrexate-based therapy. These data indicated that additional approaches are required to prevent relapses. I continue to be involved in PCNSL research at OHSU and my recent publication regarding the pattern of relapses in PCNSL identifies potential mechanism involves in relapses. Based on these studies we have now developed a clinical trial to prevent relapse in PCNSL using maintenance immunotherapy. This prospective multicenter trial is currently enrolling subjects. My recent publication in Leukemia& Lymphoma (Ambady et al; 2018) demonstrates promising preliminary data regarding the use of combination immunotherapy as a non-chemotherapy option for patients with CNS lymphoma.

1. Holdhoff M, Ambady P, Abdelaziz A, Sarai G, Bonekamp D, Blakeley J, et al. High-dose methotrexate with or without rituximab in newly diagnosed primary CNS lymphoma. Neurology. 2014;83(3):235-9. PMCID: 4117362.
2. Ambady P, Holdhoff M, Bonekamp D, Wong F, Grossman SA. Late relapses in primary CNS lymphoma after complete remissions with high-dose methotrexate monotherapy. CNS Oncol. 2015;4(6):393-8. PMCID: 4834699
3. Ambady P, Fu R, Netto JP, Kersch C, Firkins J, Doolittle ND, et al. Patterns of relapse in primary central nervous system lymphoma: inferences regarding the role of the neuro-vascular unit and monoclonal antibodies in treating occult CNS disease. Fluids Barriers CNS. 2017;14(1):16. PMCID: 5457655.
4. Ambady P, Szidonya L, Firkins J, James J, Johansson K, White T, et al. Combination immunotherapy as a non-chemotherapy alternative for refractory or recurrent CNS lymphoma. Leuk Lymphoma. 2018:1-4.

IV. Clinical Trial Investigations. These references demonstrate my previous experience in patient care in the setting of clinical trials and my ability to design and manage clinical studies

1. Campian JL, Ye X, Gladstone DE, Ambady P, Nirschl TR, Borrello I, Golightly M, King KE, Holdhoff M, Karp J, Drake CG, Grossman SA. Pre-radiation lymphocyte harvesting and post-radiation reinfusion in patients with newly diagnosed high grade gliomas. J Neurooncol 2015;124:307-16.
2. *Khan M, *Ambady P, Kimbrough D, Shoemaker T, Terezakis S, Blakeley J, et al. Radiation-Induced Myelitis: Initial and Follow-Up MRI and Clinical Features in Patients at a Single Tertiary Care Institution during 20 Years. AJNR Am J Neuroradiol. 2018;39(8):1576-81.(* equal contribution first authors)