(2ce) Biomaterial Strategies to Modulate Immunity for Disease Amelioration

Immunotherapies, i.e., therapies that target the immune system for disease treatment, have emerged as a potent curative strategy for diseases that emanate from immune dysregulation. While adaptive immunity has been at the centerstage of immunotherapy development, innate immunity is the key to activating and defining the quality of adaptive immune responses. As such, purposeful modulation of the innate immune response can unlock the full potential of the adaptive response. Given the innate immune system’s spatial and functional pervasiveness, these modulations must be precisely targeted to achieve the intended therapeutic outcomes and avoid off-target effects. Leveraging my unique background in molecular engineering, chemistry, nanotechnology, and immunobiology, I will integrate molecularly engineered polymers with nanoscale self-assembly technologies to construct immunomodulatory nanosystems to precisely drive curative innate immune responses in the context of cancer, inflammation, and autoimmunity. From stimulating anti-cancer immunity to restraining overactivity in inflammatory and autoimmune disorders, these nanosystems will tap the full therapeutic potential of the innate immune system. To illuminate the materials design criteria to build better immunotherapies, my laboratory will systematically investigate the structure-property-activity relationships at the nano/bio interface to answer these critical questions: i) how do different innate immune cells respond to exogenous physicochemical cues and integrate multiple immunological cues, and ii) how do the presentation and combination of the immune-modulating drugs affect their efficacy and safety profile? Informed by these assessments, my laboratory will develop innovative material strategies for targeted and spatiotemporally-controlled delivery of immune modulators for enhanced immunotherapeutic efficacy. The innovative drug delivery technologies will integrate interdisciplinary principles of polymer science, chemistry, and nanotechnology to drive curative immune responses.

Research Experience

Biomaterial design and drug delivery for cancer immunotherapy and vaccine, Koch Institute for Integrative Cancer Research, MIT (Advisor: Prof. Paula T. Hammond)

My postdoctoral work combines designing polymeric materials with the layer-by-layer (LbL) self-assembly technology to develop modular drug delivery platforms for more potent cancer immunotherapies and receptor-specific adjuvant targeting for cancer vaccines. Combinatorial immunotherapies that target multiple immune pathways offer a more potent strategy to improve patient outcomes. However, the increased risk of immune-related adverse events limits their utility. Optimal sequencing, timing, and duration of exposure of immune modulators that resonate with the natural immune cycle can help rescue systemic toxicity and unleash the full potency of combination immunotherapies. I am developing layer-by-layer (LbL)-assembled structures on injectable microparticles as a tractable drug delivery system to achieve appropriately-timed delivery of two immune modulators–poly(I:C), a TLR3 agonist, and interleukin-2, a pro-inflammatory cytokine–to sequentially activate the innate and sustain the adaptive anti-tumoral immunity, respectively.

The delivery route, likewise, impact the adjuvanticity of innate activators such as toll-like receptor (TLR) agonists. With increasing focus on the innate immunity to orchestrate a more potent adaptive anti-tumoral response, engineering the delivery of these immune-modulatory agents to the target receptor of choice becomes critical. My research has shown that the choice of microparticle size and polycation to bind poly(I:C) controls its adjuvanticity. Compared to the traditional polyplexes, poly(I:C)-loaded microparticles lead to enhanced activation of its cytosolic RIG-I-like receptors without compromising the activity of its endosomal TLR3 receptor. As a vaccine adjuvant, these microparticles lead to a more balanced Th1/Th2 response and enhanced antigen-specific CD8+ T cell response.

Designing polymeric materials with enhanced thermal transport and tailored thermo-responsive behavior, Macromolecular Science and Engineering, University of Michigan (Advisor: Prof. Jinsang Kim)

During my Ph.D., I established molecular design principles to develop amorphous polymeric materials with enhanced thermal conductivities. I developed chemical methods to modulate polymer chain morphology, inter-chain interactions, chain stiffening, and chain packing to achieve up to 10x higher thermal conductivities in thin amorphous polymer films. In the first system, a unique blend of H-bonding polymer pairs achieved a high concentration of strong and homogeneously distributed H-bonds that created a percolating network of efficient thermal connections. Thermal conductivity up to 1.72 Wm^-1K^-1 was achieved in nanoscale films, which is an order of magnitude higher than that of typical amorphous polymers. In the follow-up work, controlled ionization of a weak polyelectrolyte led to polymer chain extension and stiffening, and compact packing in amorphous thin films resulting in up to 6x enhancement in thermal conductivity.

Furthermore, I developed a thermo-responsive polymer-graphene oxide nanocomposite that was integrated with a microfluidic device to isolate viable circulating tumor cells from clinical blood samples of breast and pancreatic cancer patients. The isolated cells were amenable to single-cell genomic analysis, as exemplified by the identification of HER2 amplification in one breast cancer patient. These two projects with disparate applications required critical innovations in the design and synthesis of polymeric materials with tunable complexation behavior, ionizability, and temperature-controlled solubility.

Selected Fellowships and Awards

1. Mazumdar-Shaw International Oncology Fellowship ($250,000; 2 years), 2020–2022
2. Misrock Foundation Post-doctoral Fellowship ($60,000; 1 year), 2019
3. American Chemical Society (ACS) Global Outstanding Graduate Student Award in Polymer Science and Engineering (Top 5–Honorable Mention), 2019
4. ACS POLY Excellence in Graduate Polymer Research Award, 2017
5. Materials Research Society (MRS) Graduate Student Silver Award, 2016

Selected Publications and Patents (*Co-first authors)

1. Shanker, I. Bouzit, Y. He, S.T. Koshy, A. Belcher, P.T. Hammond. Comparative Assessment of Poly(I:C) Delivery Strategies to Tune its Adjuvanticity. (In preparation)
2. Erfani, J.M. Schieferstein, A. Shanker, P. Reichert, C.N. Narasimhan, P.T. Hammond, P.S. Doyle. Crystalline or Amorphous Solid Antibody Laden Alginate Hydrogel Particles: A Platform for Enabling High Concentration Subcutaneous Delivery of Biologics. (In preparation)
3. Shanker*, C. Li*, et al. High Thermal Conductivity in Electrostatically Engineered Amorphous Polymers. Science Advances 2017, 3(7), e1700342.
4. J. Yoon*, A. Shanker*, et al. Tunable Thermal-Sensitive Polymer-Graphene Oxide Composite for Efficient Capture and Release of Viable Circulating Tumor Cells. Advanced Materials 2016, 28, 4891-4897.
5. -H. Kim*, D. Lee*, A. Shanker*, et al. High Thermal Conductivity in Amorphous Polymer Blends by Engineered Interchain Interactions. Nature Materials 2015, 14, 295-300.
6. Kim, C. Li, A. Shanker, K. Pipe, G.-H. Kim. Molecularly Engineered High Thermal Conductivity Polymers and Methods for Making the Same. US patent# 10,696,885.
7. J. Yoon, A. Shanker, J. Kim, S. Nagrath, V. Murlidhar. System for Detecting Rare Cells. US patent# 10,317,406.

Teaching Philosophy and Interests

Shaped by my past experiences as a student and a teaching assistant, my student-centric teaching philosophy stands on three central pillars­¾promoting self-learning, linking the concepts learned in the class to the real world, and continuous improvement based on students’ feedback. During my Ph.D., I served as a teaching instructor for an undergraduate Materials Science and Engineering course and led recitation for a class of thirty students. To promote self-learning, I implemented the concept of ‘learning-by-doing’ for the recitation class that promoted class participation and group learning. With a strong desire to upskill my teaching abilities, I completed the Kaufman Teaching Certificate Program at MIT. The program taught me the best teaching practices and styles that I plan to integrate into my future teaching assignments. With a formal education in Industrial Chemistry and Macromolecular Science and Engineering, I am excited and qualified to teach core courses in Chemical Engineering and polymers and soft materials. Beyond these, I look forward to developing new graduate-level courses in drug delivery and immune-modulatory biomaterials.

I view empathic mentoring as the most impactful activity academics do. I have mentored ten undergraduate and graduate students over the course of my Ph.D. and postdoctoral appointment. As a mentor, I not only strive to train my mentees in laboratory work and best practices but also support their career aspirations by providing relevant resources and helping them make informed choices. I firmly believe in the cascading effect a positive experience can have to bring more students from underrepresented groups into STEM. Science wins when it’s democratized. I am committed to promoting diversity and inclusivity in my classroom and laboratory through respectful engagement and social connectedness to foster mutual learning. I look forward to bringing together cutting-edge research and the best teaching and mentoring practices to impart world-class science education and training to students at all levels.