Nano-optogenetic engineering of CAR T cells for precision immunotherapy with enhanced safety

Abstract

FDA-approved chimeric antigen receptor (CAR) T cell-based immunotherapy has shown curative potential in patients with hematological malignancies. However, owing to the lack of control over the location and duration of anti-tumor immune response, CAR T-cell therapy still faces significant safety challenges arising from cytokine release syndrome and on-target off-tumor toxicity. Herein, we present the design of light-switchable CAR T-cells (designated “LiCAR-T”) that allow real-time photo-tunable activation of therapeutic T cells to precisely induce tumor cell killing. When coupled with imaging-guided, surgically removable upconversion nanoplates (UCNPs) that have enhanced near infrared (NIR)-to-blue upconversion luminescence as miniature deep tissue photon-transducers, LiCAR T-cells enable both spatial and temporal control over T cell-mediated anti-tumor therapeutic activity in vivo with greatly mitigated side effects. Our nano-optogenetic immunomodulation platform not only provides a unique approach to interrogate CAR-mediated anti-tumor immunity, but also sets the stage for developing precision medicine to deliver personalized anti-cancer therapy.

Optophysiology: Illuminating cell physiology with optogenetics

“…Figure 6b) based on either iLID, cpLID (cpLOV2-ssrA and sspB) or CRY2-CIB1 have been developed to conditionally reconstitute a split CAR into a fully functional CAR in the presence of blue light (23,302,303). In the dark, the tumor antigen-sensing unit and/or the effector domains remain separately expressed in two constructs.…”

“…The UCNP surface can be further functionalized to coat biocompatible silica-shell, streptavidin or antibodies for cell-type-specific targeting (22,303,402). This approach is most useful when combined with adoptive cell therapies because UCNPs and engineered therapeutic cells can be co-injected to enable wireless optogenetics in living animals.…”

“…Optogenetics has also been applied to control the activity of therapeutic immune cells, such as the chimeric antigen receptor (CAR) T cells. Optogenetic or light-switchable chimeric antigen receptors (optoCARs or LiCARs; FIGURE 6 B ) based on iLID, cpLID (cpLOV2-ssrA and -sspB), or CRY2-CIB1 have been developed to conditionally reconstitute a split CAR into a fully functional CAR in the presence of blue light ( 23 , 302 , 303 ). In the dark, the tumor antigen-sensing unit and/or the effector domains remain separately expressed in two constructs.…”

CAR‐T cell therapy for lung cancer: Potential and perspective

“…Similarly, Mestermann et al 111 found that dasatinib acted as a CAR‐T cell “switch” to control the biological function of CAR‐T cells on entry into the body and protect model mice from CRS. In addition, previous studies have demonstrated that regulating the in vivo lifespan and kinetics of CAR‐T cells by optimizing CAR gene transfection 112 and using nanoparticles 113 can reduce and avoid CRS. Therefore, avoiding CRS damage after CAR‐T cell immunotherapy will be a key issue to address and focus on in the treatment of lung cancer in the future.…”

Red‐shifted optogenetics comes to the spotlight

“…As a low‐hanging fruit, REDMAP‐like devices could be readily coupled with adoptive cell therapy to develop red light‐responsive chimeric antigen receptor (CAR) T cells for cancer treatment (Figure 1C ), as recently done by using blue light‐sensitive optical dimerizers when coupled with NIR light‐activatable upconversion nanoparticles. 10 …”