Rebuilding T cells for Cancer Immunodeficiencies



 DESCRIPTION (provided by applicant): Approximately 1.7 million Americans are diagnosed annually with cancer according to the American Cancer Society. If diagnosed early, the prognosis of survival may be relatively positive for the majority of cancers using standard treatments of chemotherapy, radiation, and/or surgery. During standard treatment using chemotherapy and radiation, cancer patients experience a large destruction of lymphocytes (B, T, and NK cells). This lymphopenia, which is a type of induced secondary immunodeficiency, destroys large numbers of T cells. Without normal healthy T cell levels, the adaptive immune response will not function properly to battle newly developing neoplasias or combat further opportunistic infections. In this proposal, we aim to develop next generation protein therapeutics that will restore T cell populations to normal healthy levels quickly during the recovery of patients with lymphopenia. These new protein biologics will activate the prosurvival interleukin-7 (IL-7) signaling pathway that is essential in the development, differentiation, proliferation, and homeostasis of T cells. My laboratory has deciphered the molecular mechanisms of IL-7 signaling at atomic resolution and is now poised to translate our results into beneficial treatment strategies for human health and diseases. We hypothesize that there are IL-7 protein sequences that will function better than the native wild- type IL-7 protein sequence and possibly be able to tune specific T cell populations. We will develop these new `super IL-7' agonists by capitalizing on new technology developed in our laboratory using phage display mutagenesis that will enable us to optimize binding affinity and signaling output to its receptors in a high- throughput combinatorial approach. We will generate these new super IL-7 agonists in high protein yields and characterize their functional properties using structural, biophysical, and cell based approaches including circular dichroism, surface plasmon resonance, calorimetry, flow cytometry, and cell survival and proliferation assays. Initial studies of a subset of these protein biologics will be conducted in standard murine models to test in vivo effects. The goal at the end of the two-year funding period will be to identify super IL-7 agonists suitable for further preclinical testing in murine models through additional funding resources. These new IL-7 agonists may also find application in other states of T cell lymphopenia including sepsis and HIV infections, as new vaccince adjuvants, as ex vivo T cell enhancers for adoptive immunotherapy, and as novel immunological reagents to further delineate IL-7 immunobiology.