TR&D 3

Overview: New tools for imaging and theranostics in inflammation and cancer

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Others and we have shown that inflammation underlies the pathophysiology of a wide variety of disorders, extending from neuropsychiatric disease to infection and cancer. Within the central nervous system (CNS), neuro-inflammation is a contributing factor, if not the elemental process, behind such disparate entities as cognitive impairment due to mild, repetitive traumatic brain injury, Parkinson’s disease, dementia due to Alzheimer’s disease, HIV-related cognitive impairment and the neurological sequelae of Long Covid. Nevertheless, quantitative, non-invasive and specific tools for measurement of neuro-inflammation remain elusive. Specificity is required because inflammation may create or combat disease, depending on the cells
involved and their temporal appearance at the site of putative injury. In the periphery, inflammation plays a similarly important role in promoting or fighting cancer. In the tumor microenvironment (TME) different populations of cells, of which the innate and adaptive immune responses are comprised, enter and leave as part of a continual struggle between the host and his/her malignancy. That balance has recently been tilted toward the host in many cases, most notably through the use of immune checkpoint inhibitors. However, they and other immunotherapeutics, such as vaccines, antibody-drug conjugates and CAR T cells, are ineffective in the majority of patients to whom they are administered, and can be associated with significant adverse effects. Better understanding of inflammation in these varied contexts, i.e., the cells involved, when and to what extent, will enable design of superior agents to support the salutary aspects and reprogramming of the TME, where needed. Radiopharmaceutical therapy (RPT) is one way by which the TME might be reprogrammed. Because of the [177Lu]PSMA-617 expanded access program in the US, sufficient data are accumulating to enable appropriate patient selection, dosing regimens and prognosis for patients undergoing this effective new therapy for PSMA- expressing cancers. To address those lingering issues and emerging opportunities, we will develop and disseminate a series of reagents, according to the following aims:

Aim 1: To synthesize and optimize a small library of radiopharmaceuticals targeting the macrophage colony stimulating factor 1 receptor (CSF1R), specifically designed with 18F for dissemination and, in certain cases, for peripheral use, e.g., in cancer or infectious disease.

Aim 2: To test and validate our previously disseminated neuro-inflammation agent, [18F]FNDP, which targets soluble epoxide hydrolase, in several previously untested pre-clinical models to determine the precise cell(s) involved, and in patients with long-haul, neurological COVID (Long Covid).

Aim 3: To synthesize and test new imaging and radiotherapeutic agents targeting PSMA in tumor neovasculature and fibroblast activation protein (FAP) on cancer-associated fibroblasts (CAFs) with a view to better understanding and manipulation of the TME in clear cell renal cell carcinoma (ccRCC).

Aim 4: To develop and post on our website a platform based on artificial intelligence that will enable personalized, appropriate deployment of theranostic agents, initially trained on imaging and protected health information relevant to [177Lu]PSMA-617 as a platform.