CAR-T cell therapies have been a game-changer for treating blood cancers that were previously untreatable. However, many patients still don’t respond well to these therapies, so new approaches are needed. Researchers have now created a biodegradable scaffold material called ‘T-cell enhancing scaffolds’ (TES) that can be injected under the skin to boost the effectiveness of CAR-T cells. This intervention has shown promising results in reducing tumor growth and prolonging survival in an aggressive mouse lymphoma model.=”first” class=”lead”>CAR-T cell therapies are revolutionizing the way previously untreatable blood cancers are treated. Over 20,000 individuals have received six approved CAR-T products, and more than 500 clinical trials are currently in progress. However, a recent study from Massachusetts General Hospital found that among 100 patients with lymphomas, myelomas, or B-cell acute lymphoblastic leukemias treated with CAR-T cell therapies, only 24% experienced partial responses, and 20% did not respond at all. These success rates are typical for patients undergoing CAR-T therapy.
CAR-T cellsCAR-T cells are made from a patient’s own immune T cells. Scientists introduce “chimeric antigen receptors” to the cells, which allows them to find and destroy specific cancer cells. After being engineered and multiplied outside the body at great expense, they are given back to the patient as a living treatment. Oncologists believe that the disappointing outcome of treatments may be due to various factors, such as the low quality of the CAR-T cell products given to patients, or the cells not staying in the patient’s body long enough or becoming exhausted.CAR-T cells have limitations in their ability to fight tumors, so there is an urgent need for new therapeutic approaches to improve their quality and effectiveness. A research team at the Wyss Institute for Biologically Inspired Engineering at Harvard University and Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS) has created a biodegradable scaffold material that can be injected under the skin to re-stimulate CAR-T cells after they are administered, enhancing their therapeutic potential. This intervention aims to address the shortcomings of CAR-T cells and improve their efficacy.The team’s “T-cell enhancing scaffolds” (TES) showed significant effectiveness in curbing tumor growth and prolonging survival in mice with an aggressive blood tumor who were treated with a non-curative dose of CAR-T cells. The TES increased the numbers of CAR-T cells in the blood circulation and directed their differentiation into tumor-killing T cell subtypes, resulting in improved therapeutic efficacy. The study’s findings are published in Nature Biomedical Engineering. The researchers believe that although their strategy needs to be adapted for human needs and settings, it has the potential to offer a safe and simple solution.”This study provides a new avenue for enhancing CAR-T cell therapies in patients with poor responses,” explained David Mooney, Ph.D., a founding faculty member of the Wyss Institute who led the research. “It also has the potential to simplify the complex and costly manufacturing process of CAR-T cells by incorporating part of the process into patients’ bodies.” Mooney is also the Robert P. Pinkas Family Professor of Bioengineering at SEAS.
Various approaches to stimulating CAR-T cells have been developed, which not only introduce CAR receptors but also make other genetic modifications to the patients’ T cells in order to improve their therapeutic effects.) or targeting other components of the immune system to support CAR-T cells in their attack on tumor cells (cell-extrinsic). However, these approaches present new challenges, such as more complex manipulation of cells during CAR-T cell production and control of the cells’ behavior in the case of cell-intrinsic methods, or unintended side effects in the body in the case of cell-extrinsic methods.
Creating an artificial lymph node under the skin
“Previously, our team had developed biomaterial scaffolds that allowed T-cells to expand for immunotherapies in a culture dish by mimicking aAntigen-presenting cells (APCs) usually alter T-cells in lymph nodes by presenting tumor antigens to them. We believed that this idea could also be used to effectively stimulate CAR-T cells in the body. TES could essentially act as pseudo-lymph nodes,” stated co-first author David Zhang, who earned his Ph.D. while working in Mooney’s group.
TES biomaterial scaffolds are made up of small biodegradable mesoporous silica rods (MSRs) that form 3D, cell-permeable scaffold structures when injected under the skin and attach themselves to the blood circulation via.The tiny blood vessels, called TES, contain a soluble molecule called interleukin-2 (IL-2) that is released continuously and encourages the multiplication of T cells that enter the TES from the bloodstream. Additionally, the MSRs have a double layer of lipids that mimics the outer cell membrane of an APC that a T-cell would encounter in a lymph node. This lipid layer presents two antibody molecules, anti-CD3 and anti-CD28, to the T-cell receptor on the surface of T cells in a similar way to how APC-presented tumor antigens normally stimulate the receptors. This then prompts the CAR-T cells to increase in number and differentiate.
Researchers have discovered a way to convert engineered T cells into T cells that can kill tumors. They found the best combination of anti-CD3:anti-CD28 antibodies and quantities in TES to recruit the highest number of cultured CAR-T cells and turn them into “effector T-cells” with the ability to kill tumor cells. When injected under the skin of mice, TES connected with the animals’ vasculature and remained visible as vascularized nodules for over three weeks. Over 60% of the cells in the porous network were neutrophils, which are white blood cells that are a key part of the immune system’s initial defense against infections.The majority of immune cells present in the tumor environment were T cells, which are responsible for delayed and more specific targeting of tumor cells or pathogens. The researchers believe that TES scaffolds promote vascularization and attract specific types of immune cells by causing minor inflammation. Joshua Brockman, Ph.D., who was a Postdoctoral Fellow on Mooney’s team and is now an Assistant Professor at the University of Wisconsin-Madison, stated that the scaffolds help in actively recruiting immune cells in addition to the passive migration of cells through TES. The injected scaffolds were removed at different time intervals and cultured with CAR-T cells.The team used a clinically-relevant mouse model of human Burkitt’s lymphoma, a blood cancer caused by B-cells becoming cancerous and impacting many organs, to test TES’ potential as therapy boosters. They administered human lymphoma cells to the mice and then gave them a curative dose of CAR-T cells developed against this tumor before injecting TES under the skin of the animals. It was found that TES could stimulate CAR-T cells for at least seven days following their injection, as concluded by measuring the cells’ activation level. Importantly, TES contained the full complement of IL-2.anti-CD3 and anti-CD28 factors significantly increased the number of circulating CAR-T cells by more than five times compared to TES without these factors. These CAR-T cells also showed an enhanced ability to kill tumor cells. Even when lower doses of CAR-T cells were used, which were not enough to fully cure the cancer, the cells still multiplied.
According to Zhang, TES absorbed CAR-T cells into their porous structure, leading to increased proliferation, activation, and differentiation. This ultimately allowed the CAR-T cells to enter the bloodstream and carry out their tumor-killing functions effectively. This finding is significant as it suggests that TES can play a crucial role in enhancing the effectiveness of CAR-T cell therapy.
In experiments, animals with lymphoma that were given subcurative doses of CAR-T cells and TES that did not work well died quickly from the cancer. On the other hand, animals that were injected with CAR-T cells and fully functional TES survived for a longer period of time.
Brockman stated that the aggressive lymphoma mouse model was a good way to show proof-of-concept. However, this model represents a cancer patient in advanced stages of the disease who needs a lot of cytotoxic T cell potential for treatment. In order to make TES more suitable for human patients, it may be necessary to develop even longer-lasting and balanced approaches that also improve the CAR-T cells’ ability to remember tumors.
The research conducted by Dave Mooney’s team illustrates the potential of using engineering to replicate the interactions between multiple cells that play a crucial role in our immune system’s ability to combat cancer. According to Donald Ingber, M.D., Ph.D., the Founding Director of the Wyss Institute and the Judah Folkman Professor of Vascular Biology at Harvard Medical School and Boston Children’s Hospital, this technology has the potential to significantly impact the lives of cancer patients who are not yet experiencing the full benefits of CAR-T therapies.
Additional authors involved in the study include Kwasi Adu-Berchie, Yutong Liu, Yoav Binenbaum, Irene de Lázaro, Miguel Sobral, and Rea Tresa. The study received funding from the Wyss Institute at Harvard University, Food and Drug Administration (award# 5F01FD006589), and National Institutes of Health (award# 1R01EB015498, #R01 CA276459, and U01CA214369).
