Cell-based immunotherapies are in active development for treatment of cancer, and adoptive cell therapy (ACT) of cancer with ex vivo activated/expanded T-cells is one of the more promising treatments being currently tested in patients. However, strategies to enhance the persistence and effector functions of ACT T- cells are sought, to increase the frequency of objective responses. One way to enhance the function of ACT T- cells is via genetic engineering of the lymphocytes themselves, introducing chimeric receptors or costimulatory molecules. Here we propose a complementary strategy, based on the linkage of nanoparticle drug carriers (functionalized biodegradable polymer nanoparticles) to ACT T-cells, enabling T-cells to carry and release drug cargos in their local environment. This novel approach to tumor immunotherapy offers several potential advantages over systemic adjuvant drug therapy: (1) T-cells will be uniformly exposed to drugs designed to act directly on the ACT cells themselves, irrespective of their particular tissue location and focusing the drug action on the target cells, (2) the biodistribution of drug treatment will follow the homing of T-cells and may allow a reduction in dose and limitation of systemic toxicity, and (3) sustained action of pro-immunity or anti-tumor drugs will be achieved via sustained release from cell-bound nanoparticle (NP) drug carriers.
Our specific aims are: (1) We will determine the maximal NP load and basal persistence time of particle drug carriers attached to ACT T-cells transferred into tumor-bearing hosts. (2) We will test the hypothesis that interleukin cytokine support of ACT T-cells is augmented by T-cell-mediated delivery, compared to systemic injection of cytokine. (3) We will determine whether T-cell-mediated delivery of TLR ligands to tumors can substantially enhance ACT, and compare cell-mediated delivery to systemic TLR ligand injection. (4) We will determine whether combining delivery of antigen and TLR ligands as an in situ vaccine boost for ACT T-cells can provide substantial synergy in promoting anti-tumor responses. These studies will identify nanoparticle compositions that 'arm'T-cells for more effective anti-tumor function, by modulating either the function of T-cells themselves or cells in their local microenvironments, both tumor sites and secondary lymphoid organs. Public Health Relevance: Adoptive cell therapy is a promising strategy for cancer treatment, but combination therapy will likely be necessary to achieve eradication of advanced metastatic cancer. Here we propose an approach based on the attachment of biodegradable drug-loaded nanoparticles to T-lymphocytes, using T-cells as living drug delivery agents to carry therapeutics into lymphoid organs and tumor tissues. If successful, this method for engineering ACT T-cells would be simple to implement in the clinic and complementary to other strategies for augmenting ACT (such as T cell genetic engineering), and could potentially be extended to other therapeutic immune cell populations.
Adoptive cell therapy is a promising strategy for cancer treatment, but combination therapy will likely be necessary to achieve eradication of advanced metastatic cancer. Here we propose an approach based on the attachment of biodegradable drug-loaded nanoparticles to T-lymphocytes, using T-cells as living drug delivery agents to carry therapeutics into lymphoid organs and tumor tissues. If successful, this method for engineering ACT T-cells would be simple to implement in the clinic and complementary to other strategies for augmenting ACT (such as T cell genetic engineering), and could potentially be extended to other therapeutic immune cell populations.
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