For patients with certain types of blood cancer, a treatment called chimeric antigen receptor (CAR) T-cell therapy can be a “miracle” cure, keeping them cancer-free for many years. These “living” drugs are a type of immunotherapy that use the patient’s own immune system to fight the cancer.
In 2017, a drug called Kymriah was among the first CAR T-cell therapies to receive approval from the U.S. Food and Drug Administration (FDA) for treatment of relapsed or refractory diffuse large B-Cell lymphoma. Following that, the FDA approved more similar therapies for the treatment of various types of blood cancer. Despite the miraculous efficacy, a portion of cancer patients receiving CAR T-cell therapy will experience serious side effects, which often arise because of the lack of controlled activation over the anti-tumor immune response triggered by the engineered T-cells.
To address this challenge, researchers at the Texas A&M Health Institute of Biosciences and Technology (IBT) and the Department of Translational Medical Sciences at the Texas A&M University School of Medicine developed one type of intelligent T-cells, termed “light-switchable CAR T-cells” (or LiCAR-T), that can rapidly respond to light to switch on their tumor-killing capabilities.
Yubin Zhou, professor and Presidential Impact Fellow at the Center for Translational Cancer Research at the Institute of Biosciences and Technology, and Yun Nancy Huang, associate professor at the Center for Epigenetics and Disease Prevention, led the study developing LiCAR-T cell immunotherapy for cancer treatment. Their study was published in the journal Nature Nanotechnology.
“CAR T-cell immunotherapy has shown a high potential for tumor eradication, and the field has seen encouraging complete remission instances like Emily Whitehead and Bill Ludwig,” Zhou said. “However, CAR T-cell therapy still has some notable safety challenges because of devastating adverse effects associated with poor control over its anti-tumor activity.”
Some of these adverse side effects are cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome and the depletion of normal B cells.
“CAR T-cell therapy may cause cytokine storm due to the rapid activation of T-cells within a short time window after recognizing tumor cells. In some cases, this might send patients into the intensive care init (ICU),” Zhou said.
FDA-approved CAR T-cell therapies are mostly designed to target the CD19 antigen, which is abundantly expressed on the surface of cancer cells but is also present on normal B cells. Therefore, they lack the ability to discriminate between normal CD19-positive cells and cancerous CD19-positive cells, which could lead to a common side effect known as B-cell aplasia (depletion of leukocytes in the blood). These side effects are manifested in multiple clinical symptoms, including fever, low blood pressure, neurological changes and multi-organ failure, potentially leading to death.
“To address this issue, we came up with the idea of using light as a non-invasive means of controlling the activation of therapeutic immune cells,” said Huang, a Cancer Prevention and Research Institute of Texas (CPRIT) scholar in cancer research. “By doing so, we can selectively switch on tumor-killing immune cells within the tumor sites, but not elsewhere, to substantially reduce side effects. More impressively, the LiCAR-T platform allows us to fine-tune anti-tumor immune response by simply playing with the light pulse and intensity.”
The LiCAR-T system is built upon engineered CAR T-cells that remain inactive without photostimulation but quickly restore their tumor-killing function when illuminated by blue light.
“Functional CAR proteins can be reassembled within seconds in response to light stimulation in order to trigger T-cell activation and to execute the tumor-killing activity,” said Nhung Nguyen, a CPRIT-funded Cancer Therapeutics Training Program postdoctoral fellow in Zhou’s group who spearheaded this study. “After numerous rounds of optimization, we successfully improved the LiCAR-T system to reach maximized tumor-killing activity in a light-dependent fashion. The optimized system was rigorously tested in multiple animal models to demonstrate its ability to photo-induce cancer eradication.”
To move this technology one step further toward real-world applications, the team has to overcome the limited depth of tissue penetration (less than one millimeter) associated with visible light. The team resorted to a special type of nanomaterial, called upconversion nanoparticles. These tiny nanomaterials — which are only dozens of nanometers in size — can capture near-infrared (NIR) light that is invisible to human eyes and then converting it into visible blue light. These nanoparticles serve as injectable nano-illuminators and could be surgically removed.
“Blue light is good for activating the LiCAR T-cells in culture dishes, but it cannot effectively penetrate the body. By contrast, NIR light can easily penetrate deep into biological tissues for up to a few centimeters,” said Gang Han, professor at University of Massachusetts Chan Medical School and also a co-leader of the study. With this innovative approach, the collaborative team solved the tissue penetration problem.
“This design not only enables minimally invasive LiCAR-T therapy, but also allows tight control over the therapy by light,” said Kai Huang, the co-first author of the work. “To make the nanoparticles more effectively activate the LiCAR T-cells, we produced brighter nanoparticles by increasing their size and composition recipe. We also engineered their surface chemistry to make sure that they are safe for injection in the body. We are very excited to see nanoparticles working well in our LiCAR system and achieving precise tumor killing in multiple models of cancer.”
This biomedical engineering strategy was further validated in another study published in the journal Nature Chemical Biology, in which the team used a slightly different design with novel photoswitches.
“In these two proof-of-concept studies, immune cell engineering has been creatively coupled with material science to enable nano-optogenetic immunotherapy, whereby the time, location and duration of anti-tumor response can be remotely and wirelessly controlled by light,” Zhou said. “This is also a great example of combining interdisciplinary approaches to address side effects facing current cancer immunotherapy.
“We hope that the nano-optogenetic approach will pave the way for developing future generations of intelligent cell-based cancer immunotherapy, in which the precise control over anti-tumor immunity enables the real-time tuning of amplitude and duration of the treatment, thereby delivering personalized anti-cancer therapeutics.”