1/24/2024 0 Comments Texmacs mediaDue to cross-reactivity of our CAR T cells between human and mouse ICAM-1, the lack of on-target, off-tumor toxicity by micromolar affinity CAR T cells in mice with human tumor xenografts could be used to support specificity of our CAR T cells toward ICAM-1 high tumors in humans. This study had shown that CAR T cells with micromolar affinity rather than more typical low nanomolar affinity to antigens were able to safely eliminate anaplastic thyroid cancer cells while avoiding healthy tissues. Previously, we constructed CAR T cells possessing 10 6-fold difference in affinity to ICAM-1 (equilibrium constant, K D) from millimolar to nanomolar to find an optimal range of CAR affinity for CAR T killing to be selective to ICAM-1 high tumors 8. Although, most thyroid cancers are indolent and curable with standard treatments, 5 to 10% of patients develop progressive disease that are metastatic and refractory to current therapies 7.Īs a new treatment modality for advanced thyroid cancers, we demonstrated a single infusion of CAR T cells specific to ICAM-1 to be highly efficient in eliminating thyroid tumors in preclinical models, providing long lasting survival benefit 5. Recently, we reported a significant correlation between intercellular adhesion molecule (ICAM)-1 expression and the malignant features of thyroid cancer 5, including BRAF point mutations (V600E) 6. Due to the scarcity of targetable antigens in the solid tumor setting and concerns of off-tumor reactions of immune cells with healthy tissues, the successful application of CAR T cells to solid cancers has been limited 4. These studies support the initiation of a phase I study to evaluate the safety and potential efficacy of micromolar affinity tuned CAR T cells against newly diagnosed anaplastic and refractory or recurrent thyroid cancers.Īdoptive cellular therapy using chimeric antigen receptor (CAR) T cells has benefited from significant technological advancements and lead to impressive clinical outcomes in selected hematological malignancies 1, 2, 3. Selective anti-tumor activity in the absence of toxicity provides proof-of-concept that micromolar affinity tuned CAR T cells can be used to target tumors expressing high levels of antigen while avoiding normal tissues expressing basal levels of the same antigen. We examined cross-reactivity of CAR T cells toward both human and murine ICAM-1 and ICAM-1 expression in human and mouse tissues to demonstrate that both efficacy and on-target, off-tumor toxicity can be studied in our preclinical model. The resulting CAR T cells were formulated for cryopreservation to be used directly for infusion into patients after thawing with no further processing. Using Prodigy, thawed leukopak cells were enriched for CD4 + and CD8 + T cells, subjected to double transduction using lentiviral vector, and expanded in culture for a total of 10 days with a final yield of 2–4 × 10 9 cells. ![]() Herein, we report the automated process of CAR T cell manufacturing with CliniMACS Prodigy (Miltenyi Biotec) using cryopreserved peripheral blood leukocytes from apheresis collections. For clinical translation of this novel modality, we designed CAR T cells possessing micromolar rather than nanomolar affinity to ICAM-1 to avoid cytotoxicity in normal cells with basal levels of ICAM-1 expression. Previously, we have shown a significant correlation between ICAM-1 overexpression and malignancy in thyroid cancer, and have pioneered the use of ICAM-1 targeted CAR T cells as a novel treatment modality. While the majority of thyroid cancer patients are easily treatable, those with anaplastic or poorly differentiated recurrent thyroid carcinomas have a very poor prognosis with a median survival of less than a year.
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