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Adam C. Soloff, Ph.D.

University of Pittsburgh

Enhancing the Functionality of T cells for Next Generation Adoptive Cell Transfer Therapy for Advanced Lung Cancer

Adam C. Soloff, Ph.D.

Under the right conditions, the body’s immune system is capable of recognizing and eliminating cancerous cells in the lung and those which have metastasized to distant locations. To distinguish harmful tumor cells from healthy cells, the immune system recognizes proteins which have been altered due to mutations which occur when cells become cancerous. Lung cancers have one of the highest rates of such mutations, making these tumor cells prime targets to be destroyed by the immune system. One promising form of immune-based therapy isolates white blood cells, immune cells called lymphocytes, with potential tumor-killing abilities from tumors which have been surgically removed. These tumor-infiltrating lymphocytes are then grown to large numbers in the laboratory and transferred back to the patient. Such adoptive cell transfer (ACT) therapies have had remarkable success, resulting in roughly ~20% response rates in advanced stage cancer patients even after they have failed conventional treatments. Regrettably, although immune-based therapies have revolutionized lung cancer treatment, the vast majority of patients will not benefit from these treatments.

Our study seeks to develop the next generation of ACT therapy for lung cancer to dramatically improve response rates. Limiting ACT therapies is the need to grow the immune cells to great numbers before treatment. This rapid expansion requires a great amount of energy from the tumor-infiltrating lymphocytes, which results in cells which are exhausted and have lost the ability to eliminate tumors. Our study would overcome these limitations in two ways. First, we aim to use a unique metastatic site to harvest immune cells for therapy. When cancers spread to the chest cavity, patients may experience a buildup of fluid called malignant pleural effusion (MPE). MPEs are drained and discarded to ease discomfort. Yet, these MPEs contain billions of immune cells, many of which we have shown are capable of recognizing and killing the patient’s own lung cancer cells. By using MPEs instead of solid tumors, we are able to isolate up to 100,000 times more immune cells, allowing us to transfer these cells back to the patient without massive expansion. We believe that by not undergoing such expansion, our immune cell product would retain its ability to eliminate tumors. Next, we propose to treat immune cells isolated from MPEs with a unique drug that reprograms how the cell uses fuel (glucose) for energy. By redirecting how the cell creates its energy during the period of expansion, we feel we can allow the immune cells to divide to great numbers, while still retaining their function, resulting in better responses against tumor cells.

Building upon the ground-breaking work of those who pioneered ACT therapies, we feel our study represents a unique strategy to create a better immune cell product. We believe that our proposed treatments may yield immune cells which retain their full tumor-killing capacity and are better able to survive and multiply in the patient after delivery. If successful, our research team has the capacity to rapidly translate these findings to the treatment of our lung cancer patients immediately.

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