Programming CAR T cells to enhance anti-tumor efficacy through remodeling of the immune system

Abstract

Chimeric antigen receptor (CAR) T cells have been indicated effective in treating B cell acute lymphoblastic leukemia and non-Hodgkin lymphoma and have shown encouraging results in preclinical and clinical studies. However, CAR T cells have achieved minimal success against solid malignancies because of the additional obstacles of their insufficient migration into tumors and poor amplification and persistence, in addition to antigen-negative relapse and an immunosuppressive microenvironment. Various preclinical studies are exploring strategies to overcome the above challenges. Mobilization of endogenous immune cells is also necessary for CAR T cells to obtain their optimal therapeutic effect given the importance of the innate immune responses in the elimination of malignant tumors. In this review, we focus on the recent advances in the engineering of CAR T cell therapies to restore the immune response in solid malignancies, especially with CAR T cells acting as cellular carriers to deliver immunomodulators to tumors to mobilize the endogenous immune response. We also explored the sensitizing effects of conventional treatment approaches, such as chemotherapy and radiotherapy, on CAR T cell therapy. Finally, we discuss the combination of CAR T cells with biomaterials or oncolytic viruses to enhance the anti-tumor outcomes of CAR T cell therapies in solid tumors.

Effects of Chemotherapy Agents on Circulating Leukocyte Populations: Potential Implications for the Success of CAR-T Cell Therapies

“…We will discuss the practical implications of these observations in the next section. However, it is also worth highlighting the potential for CAR-T cells and chemotherapeutics to act synergistically by administering both types of therapy within the same timeframe [ 115 , 116 ]. This is because, in addition to the systemic effects discussed so far, chemotherapy drugs can also have diverse effects on the tumour-immune microenvironment, which can, in turn, affect local CAR-T cell activity.…”

Biological causes of immunogenic cancer cell death (ICD) and anti-tumor therapy; Combination of Oncolytic virus-based immunotherapy and CAR T-cell therapy for ICD induction

“…In B cell malignancies such as non-Hodgkin lymphoma, acute lymphoblastic leukemia, and chronic lymphocytic leukemia, treatment with CD19-specific CAR T-cell demonstrated highly promising outcomes [140]. However, the usage of CAR T-cells in solid cancers has been met with some challenges, including CAR T-cell frailty in the immunosuppressive TME, restricted trafficking capacity, heterogeneity of tumor antigens, difficulty in identifying the ideal TAA target, and reduced proliferation and persistence of CAR T-cells in tumor site [141,142]. The main goal of CAR-T immunotherapy is to alter T cells so that they can recognize and destroy cancer cells more effectively [138].…”

Auswirkungen von Chemotherapeutika auf zirkulierende Leukozytenpopulationen: Mögliche Implikationen für den Erfolg von CAR-T-Zell-Therapien

“…Was diese Beobachtungen für die Praxis bedeuten könnten, soll in diesem Abschnitt erörtert werden. Ebenso gilt es auf das Potenzial von Synergieeffekten einzugehen, wenn CAR-T-Zellen und Chemotherapeutika im gleichen Zeitrahmen verabreicht werden [115, 116]. Denn neben den bereits geschilderten systemischen Wirkungen können Chemotherapeutika auch vielfältige Auswirkungen auf die Immun-Mikroumgebung des Tumors haben, die wiederum die lokale CAR-T-Zell-Aktivität beeinflussen können.…”