(4gv) Biomaterial-Driven Immune Modulation for Cancer and Autoimmune Diseases

Dysregulation of the immune system manifests itself in different ways: impaired immune surveillance leads to cancer and microbial infections, and overactivation leads to autoimmune diseases such as multiple sclerosis and type-1 diabetes. A variety of biomaterials and drug delivery systems have successfully addressed the challenges of targeted drug delivery to treat such diseases. Nevertheless, several critical questions remain unanswered: how do different immune populations respond to external physicochemical cues, what are the downstream immune pathways activated through such interactions, and how does the timing and sequencing of immune-modulating drugs affect their efficacy and safety profile? Material-based engineering approaches grounded in immunology can help answer these questions and facilitate more potent treatments.

Building upon my research experiences, I envision leading an interdisciplinary research laboratory at the interface of materials and immunology to develop new tools to probe, understand, and address pathological conditions emanating from a dysregulated immune system. My laboratory will leverage the large design space afforded by polymers and the LbL self-assembly technology to develop material systems with controlled surface chemistry, charge, hydrophobicity, and surface ligand density for assessing biomaterial-immune cell (dendritic cells, macrophages, neutrophils, etc.) interactions and complement activation. The overarching goal will be to map the material property-immune response landscape spanning over material properties, cell and tissue types, and the duration of the interaction to inform design criteria for better immunotherapeutic modalities. Informed from 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. These technologies will be applied to two core areas:

1. Cancer immunotherapies: Effects of combining and sequencing immune-modulators will be explored in the context of T-cell activation and inhibition of immune-suppressive pathways including targeting of myeloid-derived suppressor cells and tumor-associated macrophages. Combinatorial immunotherapies with optimized dosing regimens will further be adapted to nanoparticle platforms for systemic targeting of inaccessible and disseminated tumors through intravenous injections.
2. Autoimmunity and inflammation: To overcome challenges associated with systemic immunosuppression generally employed for autoimmune treatment, material strategies for targeted delivery of antigens in the context of tolerogenic signals and immune suppressants will be developed to elicit antigen-specific tolerance.

Research Experience

Drug delivery strategies for combination immunotherapy of cancer, 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. 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 over-arching goal is to correlate therapeutic efficacy and immune activity (upregulation of chemokine genes responsible for the recruitment of effector cells in the tumor microenvironment, cytokine receptor genes, and NK and T cell function-related genes) with the sequencing and timing of the release of the LbL-delivered immune-modulators.

The delivery route can, 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. I am exploring delivery strategies such as polyplexes and nano-/microparticles to specifically target poly(I:C) to its endosomal receptor TLR3 or cytosolic receptors such as RIG-I and MDA-5. Such adjuvant engineering strategies can be combined with cytokine delivery to enhance the therapeutic efficacy of combination immunotherapies.

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

My Ph.D. work primarily involved developing molecular design principles to increase thermal transport in fully amorphous polymeric films. In collaboration with Prof. Kevin Pipe’s laboratory, I developed strategies 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. Using a unique blend of H-bonding polymer pairs, a high concentration of strong and homogeneously distributed H-bonds locally extended the morphology of the long flexible polymer and created a percolating network of efficient thermal connections. In this system, thermal conductivity reaching up to 1.72 Wm^-1K^-1 was achieved for nanoscale films, which is nearly an order of magnitude higher than that of typical amorphous polymers. In the follow-up work, controlled ionization of a weak polyelectrolyte was used to enhance thermal conductivity by up to 2x in micrometer-thick amorphous polymeric films. In collaboration with Prof. Sunitha Nagrath’s laboratory, I developed a microfluidic cell isolation device based on a thermo-responsive polymer-graphene oxide nanocomposite film. In contrast to other similar devices, the polymer composite film-based microfluidic device could operate at room temperature to capture the CTCs from blood samples and required cooling down to release the captured cells from the device. The device was successfully used to isolate viable circulating tumor cells from patient blood samples that enabled downstream single-cell analyses.

The two projects with disparate application demands required critical innovations in the design and synthesis of polymeric materials with controlled 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*, C. Li*, et al. High Thermal Conductivity in Electrostatically Engineered Amorphous Polymers. Science Advances 2017, 3(7), e1700342.
2. 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.
3. -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.
4. 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.
5. J. Yoon, A. Shanker, J. Kim, S. Nagrath, V. Murlidhar. System for Detecting Rare Cells. US patent# 10,317,406.

Teaching Philosophy and Interests

I am deeply committed to improving science education and teaching. 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 augment my teaching skills, I completed the Kauffman Teaching Certificate Program at MIT. My student-centric teaching philosophy is built on three central pillars of promoting self-learning, connection to real-world applications, and continued refinement based on student feedback. As a trained chemist and polymer scientist, I am excited and qualified to teach core courses in polymer chemistry and physics, chemical kinetics and thermodynamics. Beyond these, I look forward to developing new graduate-level courses in drug delivery and immune engineering.

1. Concepts in Drug Delivery: The foundational course in drug delivery will cover the basic concepts in designing drug delivery platforms, barriers to drug delivery, drug PK/PD and biodistribution. It will further provide a snapshot of the latest developments to orient the new graduate students.
2. Materials Approaches to Immune Engineering: This coursework will cover basic immunology and materials science to orient graduate students from diverse backgrounds for a successful graduate career in immune engineering. It will further cover the historical and latest developments in the fields of material-immune cell interactions, immune cell targeting, and drug delivery for immunotherapies of cancer and autoimmune diseases.

I view empathic mentoring as the most impactful activity academics can do. I mentored four undergraduate and graduate students during my Ph.D., and continue to actively participate as a mentor in undergraduate research opportunity programs at MIT. Mentoring students from underrepresented groups has enabled me to better understand the barriers such students face. 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 the 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 bring together cutting-edge research and the best teaching and mentoring practices to impart world-class science education and training to students at all levels.