Murthy Awarded $300K NSF Grant
ChE Professor Shashi Murthy was awarded a $300K NSF grant to create a "Bioreactor System for Autologous T-Cell Stimulation".
Abstract Source: NSF
The next major frontier in the treatment of cancer involves the use of a patient's own cells to target and destroy cancer cells and tumors. Decades of fundamental research has led to breakthroughs in the form of new therapies that are entirely personalized. The cell type that is most commonly used to target cancers is the T cell, a type of white blood cell. These cells can be modified in one of several different ways to endow them with targeting capability. One way is to use the natural mechanism by which the body responds to threats such as infections. Dendritic cells are cells that are present in multiple locations of the body; these cells are capable of identifying threats and communicating their essential characteristics to T cells, which can then destroy the infectious agents. This type of approach can also be utilized to target cancer by obtaining dendritic cells from a patient, exposing these cells to tumor-derived material, and then utilizing these cells to stimulate T cells obtained from the patient's blood. This process also causes the T cells to expand, or multiply significantly in number. These T cells are then infused back into the patient to target the patient's cancer. This approach has been found to be highly effective in cancer treatment in multiple early-stage clinical trials. However, a major challenge with this therapeutic approach is the personalized nature of the treatment. Each patient's therapy consists of his/her own cells, prepared based on his/her own cancer characteristics. Current methods require over 4,600 manual steps to prepare one therapeutic dose for one patient, which is neither practical nor cost-effective in treating large numbers of patients across the nation. This project addresses the manufacturing challenge associated with T cell stimulation with an interdisciplinary approach to design disposable stimulation systems that can accept dendritic cell and T cell samples, accomplish the desired stimulation in a timely and efficient manner, and generate enough T cells for a therapeutic dose. It is expected that the number of steps associated with the T cell stimulation process will be reduced significantly. Furthermore the process will be substantially automated to minimize manual handling. The educational impact of this project will be in the form of training for a postdoctoral scientist and multiple students in an academic-industrial collaboration.
The recent successful clinical demonstration of the immune system's ability to mediate rejection of large and established tumors represents a paradigm shift in cancer therapy that will revolutionize medicine. The ability to predict candidate neoantigens from tumor sequencing data and monitoring neoantigen-specific T-cell responses in patients provides a basis for designing personalized therapies in humans, and this approach has been effectively demonstrated by several groups recently. In this approach, T cells obtained from the patient's blood are stimulated and expanded by co-culture with antigen-presenting cells, the most potent of which are dendritic cells derived from monocytes obtained from the same patient. Deep and durable clinical responses have been achieved in several clinical studies. Yet it is widely recognized that current approaches to the manufacturing of such therapies are far from adequate and will not allow the true potential of these therapies to be broadly realized across our society. Manual cell culture techniques remain the mainstay of production, which is neither practical nor cost-effective. This project aims to address the unmet need for efficient T cell stimulation technologies by a combination of automation and next-generation bioreactor design. The Bioreactor for Autologous T Cell Stimulation (BATON) system will leverage recent advances in fluidic systems as well as mass transport and will be designed in a tight-knit collaborative effort by immunologists at Neon Therapeutics and engineers at Northeastern University. The BATON system features a highly modular design with fully disposable components including disposable pumps and on-board reagent storage. This design will enable large numbers of such units to be used in parallel to process samples from multiple patients, with the users only needing to perform a total of about 180 steps per patient dose. This project addresses a critical need in the manufacturing process of personalized T cell therapies. Closed system processing is highly desired for the scalable manufacturing of such therapies, but such processing systems are difficult to design because of the complex biological processes associated with T cell therapy production as well as the bioprocess and regulatory requirements associated with autologous cell processing. The interaction between T cells and dendritic cells is a precise process with tight constraints with respect to biochemical and physical parameters. These conditions must be replicated in the design of the proposed automated system, requiring careful experimental design supplemented by computational modeling. This project is expected to overcome a major impediment to effective manufacturing of autologous T cell therapies for cancer.