(3id) Re-engineering immunomechanics in human disease to improve therapeutic outcomes

My overall research goal is to apply the fundamental concepts and methodologies of engineering to biomedicine in order to answer key questions about the underlying mechanisms of intractable human diseases, and to discover new and translatable treatment approaches. My broad experiences have provided me with rigorous training in multiple fields of academic research including chemical and biological engineering, molecular and cellular biology, biomechanics, and immunology. I utilize cutting-edge, mechanism-based research approaches to investigate a variety of abnormal tissue microenvironments that, surprisingly, often share unifying and targetable features regardless of disease etiology (infection, genetic aberrancies, or cancer). By elucidating the chemical, biological, and physical aberrancies underlying these diseases, new therapeutic strategies can be designed to “re-engineer” abnormal tissue microenvironments to improve outcomes for patients.

Successful Proposals:

AACR-Loxo Oncology Postdoctoral Fellowship (2019-2021; single-recipient grant); NIH F31 NRSA Predoctoral Fellowship (2016-2018).

Research Experience:

As described below under my doctoral and postdoctoral training, my contributions to science are based on my ability to apply unifying engineering-based concepts to tackle biomedical questions across a spectrum of diseases. These accomplishments include:

• Deconstructing the brain tumor microenvironment and underlying immunity to improve treatment response
• Development of new models and methods to measure and study tumor mechanopathology
• Identifying and overcoming physiological barriers to treatment in non-cancerous diseases
• Mathematical modeling of underlying biological phenomena in disease

Doctoral Training:

I earned my Ph.D. in chemical and biological engineering from Tufts University in 2018, with the dissertation, “Overcoming Transport Barriers in Tuberculosis Granulomas to Improve Drug Delivery”. In my doctoral training, under the supervision of Dr. Rakesh K. Jain at Massachusetts General Hospital (MGH), I discovered that pulmonary tuberculosis granulomas harbor an abnormal vasculature that can be re-engineered to improve drug delivery (PNAS, 2015; ABME, 2016). I also contributed substantially to the development of new methods to: i) measure aberrant mechanical forces in cancer and other diseases (Nat. Biomed. Eng., 2016; Nat. Protoc., 2018), and ii) target the brain tumor microenvironment to improve treatment outcomes (PNAS, 2018).

Postdoctoral Training:

In my postdoctoral training under Dr. Jain at MGH and Harvard Medical School (HMS), I am expanding my training in re-engineering the tumor microenvironment to improve response to novel immunotherapies, which have revolutionized cancer treatment, yet fail to benefit the majority of patients. In collaboration with clinicians, biologists, and engineers, I have led and contributed to projects on: i) overcoming abnormal mechanics in brain tumors (Nat. Biomed. Eng., 2019; Nat. Protoc., 2020; submitted as NIH K22) and ovarian cancer, and ii) improving response to immunotherapy in brain tumors and liver cancer (Hepatology, 2019). I am also leading projects on new approaches to: i) measure mechanical biomarkers in brain tumor patients, and ii) rationally design of host-directed therapies to improve anti-tuberculosis drug efficacy.

Future Directions:

The goal of my research program will be to “re-engineer immunomechanics in human disease to improve therapeutic outcomes.” My future program, at the interface of engineering and biology, will reveal the mechanisms by which abnormal tissue microenvironments promote disease progression and treatment resistance, and reveal new vulnerabilities that can be targeted in novel, clinically translatable treatment strategies. My first projects will focus on brain tumors as that is my most recent and expansive research area. In the future, based on my diverse experiences, I plan to expand my program across multiple diseases – including other cancers, benign tumors, infectious diseases, and autoimmune disorders – with a single unifying philosophy: combining engineering with biomedicine to address unmet needs to improve lives. I will foster both multidisciplinary and multiscale research achieved via mechanistic and translational approaches to elucidate and interrupt interactions between cancer cells, immune cells, and mechanical forces in abnormal tissue microenvironments. I will develop novel in silico, in vitro, ex vivo, and in vivo models of cancer and other diseases to recapitulate the chemical, biological, and physical abnormalities found in those tissue microenvironments. These will allow for in-depth and robust cellular and molecular mechanistic research, which will reveal new targets for translational studies, with a particular focus on FDA-approved drugs that can be harnessed for new and readily translatable therapeutic strategies.

Teaching Experience and Interests:

As part of my graduate training, I was a teaching assistant in undergraduate-level “Reaction Kinetics” and graduate-level “Bioengineering” courses, where I led weekly recitations, held office hours, and assisted students in homework and exam preparation. In my postdoctoral position, I: i) organize a weekly seminar series; ii) participate as an instructor in our laboratory’s annual “Methods in Biomedical Engineering” course with lectures, workshops, and technical demonstrations; and iii) serve as a teaching assistant and organizer for a continuing medical education course, “Critical Issues in Tumor Microenvironment: Angiogenesis, Metastasis, and Immunology.” I have also trained and co-mentored 6 graduate students and 10 junior postdoctoral fellows in laboratory skills, project establishment and management, manuscript preparation, and grantsmanship. In my future faculty position, I plan to leverage my multidisciplinary expertise to train and educate rising scientists at all levels. My curricula will focus on main concepts and “big picture” ideas in simple language with active and project-based learning components whenever possible to readily inspire creative and innovative problem-solving. I will foster an energetic and exciting classroom, and constantly engage with students by promoting open discussions. In addition to being able to teach any core courses offered by a chemical/biological engineering department, I would also be able to develop new courses that would appeal both to inter- and intra-departmental students. These courses would be related to my multidisciplinary research and would cover such topics as, “Transport Phenomena in Biological Systems,” “Mechanopathologies,” and “Engineering applications in biomedicine.”

Selected Publications:

1. Nia H.T.*, Datta M.*, Seano G.*, Ho W.W., Roberge S., Huang P., Munn L.L. and Jain R.K. (2020) “In vivo compression and imaging in the brain to measure the effects of solid stress,” Nature Protocols, E-pub ahead of print: https://doi.org/10.1038/s41596-020-0328-2. (* = equal contributions.)
2. Datta M., Coussens L.M., Nishikawa H., Hodi F.S., and Jain R.K. (2019) “Reprogramming the Tumor Microenvironment to Improve Immunotherapy: Emerging Strategies and Combination Therapies,” American Society of Clinical Oncology Educational Book, 39: 165-174.
3. Shigeta K*., Datta M.*, Hato T.*, Kitahara S.*, Chen I.X., Mamessier E. Matsui A., Ramijiawan R.R., Aoki S., Ochiai H., Bardeesy N., Huang P., Cobbold M., Zhu A.X., Jain R.K., and Duda D.G. (2019) “Dual programmed death receptor-1 and vascular endothelial growth factor receptor-2 blockade promotes vascular normalization and enhances anti-tumor immune responses in HCC,” Hepatology, 7: 1247-1261. (* = equal contributions.)
4. Seano G.*, Nia H.T.*, Emblem, K.E.*, Datta M., Ren J., Krishnan S., Kloepper J., Pinho M.C., Ho W.W., Ghosh M., Askoxylakis V., Ferraro G.B., Riedemann L., Gerstner E.R., Batchelor T.T., Wen P.Y., Lin N.U., Grodzinksy A.J., Fukumura D., Huang P., Baish J.W., Padera T.P., Munn L.L., and Jain R.K. (2019) “Solid stress in brain tumours causes neuronal loss and neurological dysfunction and can be reversed by lithium,” Nature Biomedical Engineering, 3: 230-245. (* = equal contributions.)
5. Nia H.T.*, Datta M.*, Seano G., Munn L.L., and Jain R.K. (2018) “Quantifying solid stress and elastic energy from excised or in situ tumors,” Nature Protocols 13: 1091-1105. (* = equal contributions.)
6. Arvanitis C.*, Askoxylakis V.*, Guo Y., Datta M., Kloepper J., Ferraro G.B., Bernabeu M.O., Fukumura D., McDannold N., and Jain R.K. (2018) “Mechanisms of enhanced drug delivery in brain metastases with focused ultrasound-induced blood-tumor barrier disruption,” Proceedings of the National Academy of Sciences, 115: E8717-E8726. (* = equal contributions.)
7. Nia H.T., Seano G., Liu H., Datta M., Jones D., Rahbari N., Incio J., Chauhan V.P., Jung K., Martin J.D., Askoxylakis V., Padera T.P., Fukumura D., Boucher Y., Hornicek F.J., Grodzinsky A.J., Baish J.W., Munn L.L., and Jain R.K. (2016) “Solid stress and elastic energy: new measures of tumor mechanopathology,”Nature Biomedical Engineering 1: 1-11.
8. Datta M., Via L.E., Chen W., Baish J.W., Xu L., Barry C.E., and Jain R.K. (2016) “Mathematical Model of Oxygen Transport in Tuberculosis Granulomas,” Annals of Biomedical Engineering 44: 863-872.
9. Datta M.*, Via L.E.*, Kamoun W.S.*, Liu C., Chen W., Seano G. Weiner D.M., Schimel D., England K., Martin, J.D., Gao X., Xu L., Barry C.E., and Jain R.K. (2015) “Anti-VEGF treatment normalizes tuberculosis granuloma vasculature and improves small molecule delivery,” Proceedings of the National Academy of Sciences 112: 1827-1832. (* = equal contributions.)
10. Datta M., Jackson M.D., and Datta R. (2011) “Of Mice and Men: Their Diet, Metabolism, and Weight Change,” Chemical Engineering Science 66: 4510-4520.

Keywords: Tumor Microenvironment, Cancer Immunotherapy, Biological Transport Phenomena, Mechanopathology