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Advancing chimeric antigen receptor (CAR)-engineered adoptive T cells for the treatment of solid cancers is a major focus in the field of immunotherapy, given impressive recent clinical responses in hematological malignancies. Prostate cancer may be amenable to T cell-based immunotherapy since several tumor antigens, including prostate stem-cell antigen (PSCA), are widely over-expressed in metastatic disease. While antigen selectivity of CARs for solid cancers is crucial, it is problematic due to the absence of truly restricted tumor antigen expression and potential safety concerns with “on-target off-tumor” activity. Here, we show that the intracellular co-stimulatory signaling domain can determine a CAR's sensitivity for tumor antigen expression. A 4-1BB intracellular co-stimulatory signaling domain in PSCA-CARs confers improved selectivity for higher tumor antigen density, reduced T cell exhaustion phenotype, and equivalent tumor killing ability compared to PSCA-CARs containing the CD28 co-stimulatory signaling domain. PSCA-CARs exhibit robustin vivoanti-tumor activity in patient-derived bone-metastatic prostate cancer xenograft models, and 4-1BB-containing CARs show superior T cell persistence and control of disease compared with CD28-containing CARs. Our study demonstrates the importance of co-stimulation in defining an optimal CAR T cell, and also highlights the significance of clinically relevant models in developing solid cancer CAR T cell therapies. [ABSTRACT FROM AUTHOR]

Human CD8+effector T cells derived from CD45RO+CD62L+precursors enriched for central memory (TCM) precursors retain the capacity to engraft and reconstitute functional memory upon adoptive transfer, whereas effectors derived from CD45RO+CD62L−precursors enriched for effector memory precursors do not. Here we sought to compare the engraftment fitness and function of CD8+effector T cells derived from CD45RA+CD62L+precursors enriched for naïve and stem cell memory precursors (TN/SCM) with that of TCM. We found that cytotoxic T cells (CTLs) derived from TCMtranscribed higher levels of CD28, FOS, INFγ, Eomesodermin (Eomes), and lower levels of BCL2L11, maintained higher levels of phosphorylated AKT, and displayed enhanced sensitivity to the proliferative and anti-apoptotic effects of γ-chain cytokines compared to CTLs derived from TN/SCM. Higher frequencies of CTLs derived from TCMretained CD28 expression and upon activation secreted higher levels of IL-2. In NOD/ScidIL-2RγCnullmice, CD8+TCMderived CTLs engrafted to higher frequencies in response to human IL-15 and mounted robust proliferative responses to an immunostimulatory vaccine. Similarly, CD8+TCMderived CD19CAR+CTLs exhibited superior antitumor potency following adoptive transfer compared to their CD8+TN/SCMderived counterparts. These studies support the use of TCMenriched cell products for adoptive therapy of cancer. [ABSTRACT FROM PUBLISHER]

Human CD8 + effector T cells derived from CD45RO + CD62L + precursors enriched for central memory (T CM ) precursors retain the capacity to engraft and reconstitute functional memory upon adoptive transfer, whereas effectors derived from CD45RO + CD62L - precursors enriched for effector memory precursors do not. Here we sought to compare the engraftment fitness and function of CD8 + effector T cells derived from CD45RA + CD62L + precursors enriched for naïve and stem cell memory precursors (T N/SCM ) with that of T CM . We found that cytotoxic T cells (CTLs) derived from T CM transcribed higher levels of CD28, FOS, INFγ, Eomesodermin (Eomes), and lower levels of BCL2L11, maintained higher levels of phosphorylated AKT, and displayed enhanced sensitivity to the proliferative and anti-apoptotic effects of γ-chain cytokines compared to CTLs derived from T N/SCM . Higher frequencies of CTLs derived from T CM retained CD28 expression and upon activation secreted higher levels of IL-2. In NOD/ Scid IL-2RγC null mice, CD8 + T CM derived CTLs engrafted to higher frequencies in response to human IL-15 and mounted robust proliferative responses to an immunostimulatory vaccine. Similarly, CD8 + T CM derived CD19CAR + CTLs exhibited superior antitumor potency following adoptive transfer compared to their CD8 + T N/SCM derived counterparts. These studies support the use of T CM enriched cell products for adoptive therapy of cancer.