Chimeric PD-1:28 Receptor Upgrades Low-Avidity T cells and Restores Effector Function of Tumor-Infiltrating Lymphocytes for Adoptive Cell Therapy

Abstract

Inherent intermediate-to low-affinity T-cell receptors (TCR) that develop during the natural course of immune responses may not allow sufficient activation for tumor elimination, making the majority of T cells suboptimal for adoptive T-cell therapy (ATT). TCR affinity enhancement has been implemented to provide stronger T-cell activity but carries the risk of creating undesired cross-reactivity leading to potential serious adverse effects in clinical application. We demonstrate here that engineering of low-avidity T cells recognizing a naturally processed and presented tumor-associated antigen with a chimeric PD-1:28 receptor increases effector function to levels seen with high-avidity T cells of identical specificity. Upgrading the function of low-avidity T cells without changing the TCR affinity will allow a large arsenal of low-avidity T cells previously thought to be therapeutically inefficient to be considered for ATT. PD-1:28 engineering reinstated Th1 function in tumor-infiltrating lymphocytes that had been functionally disabled in the human renal cell carcinoma environment without unleashing undesired Th2 cytokines or IL10. Involved mechanisms may be correlated to restoration of ERK and AKT signaling pathways. In mouse tumor models of ATT, PD-1:28 engineering enabled low-avidity T cells to proliferate stronger and prevented PD-L1 upregulation and Th2 polarization in the tumor milieu. Engineered T cells combined with checkpoint blockade secreted significantly more IFNg compared with T cells without PD-1:28, suggesting a beneficial combination with checkpoint blockade therapy or other therapeutic strategies. Altogether, the supportive effects of PD-1:28 engineering on T-cell function make it an attractive tool for ATT. Cancer Res; 77(13); 3577-90. Ó2017 AACR.

T-cells “à la CAR-T(e)” – Genetically engineering T-cell response against cancer

“…Consistent with previous results, no improvement in in vitro cytotoxicity was observed though this switch receptor did contribute to higher cytokine secretion and improved in vivo function in comparison to CAR alone. Lastly, Noessner and colleagues [226] demonstrated that low-affinity TCR engineered T cells as well as TILs (i.e. not CAR or TCR engineered) could benefit from the expression of the PD1/ CD28 chimera we previously designed [115].…”

Chimeric antigen receptor T cells targeting PD-L1 suppress tumor growth

“…The expression of PD-L1, which serves as a ligand for PD1 on T cells to protect tumor cells from immune control mediated by T cells, is elevated in many types of solid tumors [50]. Compared with anti-PD1 and anti-PD-L1 antibodies, several groups have reported the modi cation of traditional CAR-T cells with a PD1 switching receptor containing a CD28 intracellular domain [37][38][39]. These CAR-T cells convert PD-L1 inhibitory signals into CD28 co-stimulatory signals, which protect CAR T cells from PD-L1 mediated suppression.…”

“…Moreover, the ablation of PD-1 improves the persistence of TCR-T cells in patients with solid tumors [36]. Besides diminishing the PD-1/PD-L1 axis, a chimeric switch-receptor comprising the truncated extracellular domain of PD-1 and the transmembrane and cytoplasmic signaling domains of CD28 augments the e cacy of CAR-T cells in solid tumors [37][38][39]. Nevertheless, modi ed T cells in these studies still rely on transgenic TCR or CAR or their own TCR to recognize TSA in tumors.…”

Overhauling CAR T Cells to Improve Efficacy, Safety and Cost

“…One way of interfering with the PD-1 signaling circuit in T lymphocytes is to outcompete endogenous PD-1 mediated inhibition by expressing a fusion protein consisting of the extracellular domain of PD-1 and the signaling domains currently used in CARs (i.e., CD28). By doing so, different groups have shown a dominant positive effect on T cell activation, overcoming PD-1 inhibition in T lymphocytes [ 50 , 51 , 52 ]. T cells expressing PD1:CD28 chimera showed increased effector function, with enhanced production of interferon (IFN)-γ and increased proliferation, suggesting that this approach can effectively convert an inhibitory signal to a positive one.…”