Education and Professional Standing
Postdoctoral Research Associate, Organic Chemistry and Synthetic Immunology, Yale University 2016
PhD Organic Chemistry and Chemical Biology, University of Toronto 2012
MSc Biological Chemistry, University of Guelph 2006
BSc Biochemistry, McMaster University 2003
The Rullo Chemical Immunology Research Program at McMaster University is focused on combining the tools of organic chemistry and immunobiology to develop new molecular approaches capable of interrogating and modulating the intricate host immune-cancer cell interactome. The potential to harness the innate ability of the human immune system to selectively seek and destroy cancer cells in a manner akin to how it naturally combats most human bacterial and viral infections, represents a powerful anti-cancer therapeutic strategy. This strategy has recently materialized to afford both FDA approved immunotherapeutic drugs in addition to promising therapies currently being evaluated in clinical trials including anti-tumor vaccines, adoptive cell transfer therapies, and immunomodulatory checkpoint inhibitors. Although these immunotherapies can potentially serve to quite effectively complement and in certain ways improve on the current standards of care including cytotoxic chemotherapeutics, their ability to completely eradicate solid tumors and confer long term increases in patient survival has been limited. Such limitations arise in large part, due to a number of complex tumor evasion mechanisms combined with difficulties in our ability to discriminate the cancer cell surface from that of normal healthy cells to affect selective tumor targeting.
For the above reasons, our overarching goal is to devise, adapt and apply specific chemical strategies to diversify, expand, and advance the current immunotherapeutic arsenal while equipping it with the capacity to more effectively combat the obstacles imposed by the tumor and its extracellular microenvironment. Towards this end, we are currently developing high precision chemical strategies to probe unique molecular signatures of the cancer cell surface and aspects of the tumor microenvironment, and exploit them for recognition by a combination of host immunological machinery and chemical/ biologic immunotherapeutics.
These strategies can be divided into and described by the following three general platforms comprising the current research program.
The development of a covalent re-engineering strategy to modulate immune function
In order to promote the immunological recognition of cancer cells escaping detection, one of our key objectives involves the development of methods to covalently modify immunological machinery with established cancer cell binding motifs. To achieve this goal, we are designing ligand directing-protein labeling small molecules capable of binding to discrete locations on immunological machinery such as the antigen binding site on endogenous hapten specific antibodies and activating receptors on the surfaces of natural killer and T-cells. Through binding induced proximity effects, bio-orthogonal covalent modification of the target protein with cancer cell binding ligands can occur site specifically in the presence of complex biological environments. The resulting endogenous antibody or immune effector cell, now permanently covalently re-engineered or “chemically programmed” directly in vivo, can seek out and destroy the evasive cancer cell via a number of innate cytotoxic mechanisms. In parallel, we are also adapting synthetic covalent immunomodulators to covalently “flag” the cancer cell directly by chemically modifying receptors associated with metastatic potential and tumor immune evasion mechanisms, with immunogenic molecules. This non-reversible and stable covalent modification requiring relatively low concentrations of chemical reagent, is expected to enhance recognition of the cancer cell by both innate and adaptive arms of the host immune response affecting the redirection of cytotoxic function selectively against metastatic cancer cells.
Dr Rullo's PubMed
The generation of avidity-driven cell targeting oligomers
Exploiting structural and molecular features such as receptors uniquely associated with the cancer cell surface, to target with immunotherapeutics remains a critical challenge in current pharmaceutical immuno-oncology efforts. Tumor associated antigens (TAAs) represent a promising extracellular therapeutic target as they are generally over-expressed on the surface of metastatic cancer cells relative to their expression levels on the surface of normal healthy cells. Although essentially impossible to discriminate individual TAAs on a cancer cell from those on a normal cell via small molecule-TAA binary interactions, differences in TAA expression levels and the corresponding change in cell surface density and intermolecular TAA spacing might be differentiated using synthetic multivalent oligomers. These defined chemical structures composed of repeating synthetic units can be designed to contact several TAAs simultaneously on a cancer cell and therefore bind the corresponding cancer cell with a substantially higher avidity than it would a normal healthy cell. To exploit TAA expression density as a potential therapeutic target, we are engaged in developing libraries of sequence and structurally defined multifunctional oligomeric chemical compounds equipped with known TAA binding ligands that differ in the conformational rigidity of the oligomer and the spatial display of the associated tethered TAA ligands. Tumor cell selective oligomers identified will then be further equipped to contain small molecule or peptidic ligands against CD3 and CD16 activating receptors possessing the ability to redirect host natural killer (NK) and cytotoxic T cell function against the cancer cell yielding a new class of block copolymer immunotherapeutics.
Approaches towards Tumor Associated Carbohydrate Antigen (TACA) selective ligand development
TACAs are largely regarded as bonafide tumor specific antigens because they are completely absent from the surface of normal healthy cells and as such, represent highly strategic potential cancer therapeutic targets. Due to several reasons including their high degree of structural complexity however, there is a current lack of available synthetic ligands capable of selectively recognizing TACAs. With the goal of developing a robust method capable of efficiently generating high affinity TACA selective ligands that are stable in vivo, we aim to integrate principles underlying the molecular recognition of carbohydrates by a combination of synthetic receptors and the peptidic binding sites on cognate antibodies and lectins, with template directed dynamic covalent chemistry to generate peptidomimetic ligands. These chemically and enzymatically stable peptidomimetic ligands intended to “mimic” amino acid side chain functionality and native amide bond backbone structure, will be derived from appropriately functionalized synthetic building blocks capable of self-assembling into the optimal binding ligand when thermodynamically “selected” or templated by the TACA target. Due to the fact that TACAs are naturally part of complex glycoproteins such as mucins and lack known defined binding sites, the ability to use the mucin itself to select its own best ligand could represent a powerful strategy to discover and generate synthetic peptidomi-metic ligands capable of recognizing these unique and highly desired therapeutic targets.
What we offer
The interdisciplinary and collaborative nature of our research program presents a unique opportunity for students and aspiring scientists coming from diverse academic backgrounds to immerse themselves in key aspects of both the physical and biological sciences with the chance to conduct a combination of fundamental basic and translational research. In addition to acquiring theoretical and practical expertise across chemical biology, organic chemistry, and immunobiology disciplines, members of the group can further benefit from exposure directly within the faculty of health sciences, to workflows, protocols, and instrumentation, translating to experience highly relevant to industrial research settings. Finally and arguably most exciting is the self gratification and comradery enjoyed by members of a team that together can surmount challenging obstacles imposed by difficult and critical problems standing between them and the possibility of improving the quality of human life.