SOMATOSTATIN RECEPTOR TYPE 2 (SSTR2) FOR ADOPTIVE T CELL IMAGING, STIMULATION, AND ELIMINATION
Harnessing the immune system to recognize and destroy tumor cells has been the central goal of anti-cancer immunotherapy. Adoptive cell therapy (ACT) is a treatment that uses a cancer patient's own T lymphocytes with anti-tumor activity, expanded in-vitro and re-infused into the patient. The ability to genetically engineer human lymphocytes and use them to mediate cancer regression in patients, which has recently been demonstrated, has opened possibilities for the extension of ACT immunotherapy to patients with a wide variety of cancer types and is a promising new approach to cancer treatment. Clinical monitoring of ACT utilizes serial blood analyses to discern T cell activity. While useful, these data are 1-dimensional and lack spatiotemporal information related to treatment efficacy or toxicity. In this dissertation, I have utilized a human genetic reporter, somatostatin receptor 2 (SSTR2), and PET, to quantitatively and longitudinally visualize whole-body T cell distribution and antitumor dynamics using a clinically approved radiotracer. Initial evaluations determined that SSTR2-expressing T cells were detectable at low densities with high sensitivity and specificity. While keeping a close eye on the status of immunotherapy is shown in the early part of this thesis, later topics address the ideal antigens to target tumors, more specifically targeting solid tumors. We turned to targeting inflammation, specifically intercellular adhesion molecule-1 (ICAM-1), as an ideal marker for solid tumors. ICAM-1, which has been implicated to play a critical role in tumor progression in various types of cancer, has also been linked to cancer metastases, where this molecule facilitates the spread of metastatic cancer cells to secondary sites. The unique expression profile of ICAM-1 throughout solid tumor microenvironment makes ICAM-1 an intriguing molecular target, as evidence suggests that approximately 25% of all human cancer worldwide is associated with chronic inflammation. Utilizing ICAM1 as a target, I share the success of using an ICAM1 specific chimeric antigen receptor (CAR) T cells to eliminate anaplastic thyroid cancer tumors, in a solid tumor mouse model. The first attempt was using the single-chain fragmentvariable of R6.5, an ICAM-1 specific antibody. Followed by the utilization of the active domain (I-domain) of the natural ligand to ICAM-1, lymphocyte function associated antigen-1 (LFA-1). For I-domain CAR, many engineered affinity variants were studies, to help determine the ideal antigen to affinity, to maintain CAR T cell persistence without any systemic toxicities sometimes observed with ACTs.
Adoptive Cell Therapy (ACT); Chimeric Antigen Receptor (CAR) T cells; Inflammation and Cancer; Intercellular Adhesion Molecule-1 (ICAM-1); Positron emission tomography (PET); Somatostatin Receptor 2 (SSTR2); Biomedical engineering; Immunology; Chemical engineering
Nikitin, Alexander; Putnam, David A.
Ph. D., Biomedical Engineering
Doctor of Philosophy
Attribution-NonCommercial-NoDerivatives 4.0 International
dissertation or thesis
Except where otherwise noted, this item's license is described as Attribution-NonCommercial-NoDerivatives 4.0 International