CAR T-Cell Therapy Hydrogel Cures Cancer in Mouse Models
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Engineers from Stanford University have created an injectable hydrogel that can be loaded with immune cells to enhance CAR T-cell therapy for solid tumors. Their work is published in Science Advances.
A brief history of cancer treatment
The burden of cancer incidence and mortality continues to rise across the globe, accounting for almost 10 million deaths in 2020. Thanks to our increased understanding of human and cancer biology, the landscape of cancer treatment has evolved dramatically over the last century.
The discovery and clinical application of cytotoxic drugs – like chemotherapy – bolstered our ability to combat cancer. However, the inability of chemotherapy to distinguish between healthy and cancerous cells led to patients experiencing adverse side effects, limiting their quality of life.
A new era in cancer treatment
In the latter part of the 20th century, it became increasingly clear that a “one-size-fits-all” approach to cancer treatment was unrealistic. Advances in DNA sequencing and our understanding of the human immune system had revealed the heterogenic nature of cancer, both between individuals and between the cells of one patient’s tumor.
Cancer treatment entered a “new era”. Research focused on developing targeted, personalized therapies that consider the individual’s unique biology and that of their cancer. Immunotherapy, a form of treatment that harnesses the immune system to fight disease, emerged. The immune system is quick to adapt and highly specific, arguably a perfect match for cancer’s dynamic behavior and heterogeneity.
Get to know the human immune system
The immune system enables our body to recognize and attack foreign substances by identifying proteins present on the foreign substance’s surface.
These proteins – most commonly antigens – trigger the production of immune cells that bind to the foreign substance and instigate neutralization or cell death.
A simple analogy for thinking about this process is a lock and key. Locks can only be opened by specific keys. Similarly, antigens can only be bound by specific immune cell receptors.
Cancer cells possess antigens, but if your immune cells do not have the right immune cell receptor, or “key”, they cannot bind to the cancer cell and destroy it. Or at least they couldn’t until the advent of CAR T-cell therapy.
“CAR T-cell therapy involves taking a patient’s own T cells and engineering them to have a specific receptor (a Chimeric Antigen Receptor – CAR) that can recognize and attack cancer cells,” explains Dr. Eric Appel, assistant professor of materials science and engineering at Stanford University. “The engineered cells are then grown outside the body to great numbers and delivered back to the patient as treatment.”
Drawbacks of CAR T-cell therapy
CAR T-cell therapy, considered a “revolutionary new pillar in cancer treatment,” has seen great clinical success in the treatment of hematological cancers, such as B cell leukemia and lymphomas.
However, the same success has not been mirrored in the treatment of solid tumors. A big challenge here is the delivery of the engineered T cells, explains Appel: “Solid tumors are highly local and dense environments that immune cells have a challenging time finding and infiltrating. They also often contain suppressive immune cells and signals that leave the T cells that do make it into the tumors exhausted, and unable to attack the cancer cells.”
While scientists are working on optimizing CAR T-cell therapy, many groups are focusing on the front end of the problem, according to Appel: “Most research today is focused on engineering better CARs for specific tumor types. This is because part of the problem revolves around the T cells recognizing the cancer cells and being activated to kill them.”
Appel’s lab at Stanford University integrates concepts and approaches from supramolecular chemistry, synthetic materials and biology to tackle two areas of importance to society: advanced materials and health.
Recently, they set their sights on improving the delivery of existing CAR T-cells, with a focus on expanding greater numbers within the body that work more efficiently at recognizing and killing tumors. Their solution? A hydrogel.
A hydrogel house living on a cancerous street
Currently, CAR T-cell therapy is delivered intravenously by a drip. This results in systemic absorption of the therapy, which can make it difficult for enough of the therapy to recognize and enter solid tumors.
Appel and colleagues worked to create a water-filled hydrogel that could “house” the CAR T cells and be administered in the neighborhood of the solid tumor. This hydrogel house offers a safe environment for the engineered immune cells to grow and release over time, attacking the tumor.
The hydrogel – called Polymer-Nanoparticle (PNP)-1-5 hydrogel, or PNP-1-5 – is made up of water, a polymer created from cellulose and nanoparticles that biodegrade. “PNP hydrogels are ideal for translational use because they are simple to make and highly scalable, while they also demonstrate great efficacy for several biomedical applications, including controlled delivery of pharmaceuticals and/or cells, like in this study,” says Abigail Grosskopf, a PhD student in chemical engineering at Appel’s lab and the study’s lead author. “The material is easily injected with a syringe and needle, and then forms a robust depot after delivery that dissolves away over time, enabling long-term delivery of entrapped cargo.”
In addition to the CAR T cells, the researchers also loaded the hydrogels with cytokines, signaling proteins that are required to activate the engineered immune cells to destroy the tumor. The hydrogel enables the administration of a cytokine concentration that would usually be toxic when delivered intravenously.
CAR T-cell therapy loaded hydrogel cures cancer in mouse models
Once the research team were happy with the formulation of the hydrogel, they embarked on pre-clinical tests in animal models of cancer. “We used a subcutaneous human solid tumor in humanized mice with human CAR T cells,” says Grosskopf. A humanized mouse is one that has been genetically manipulated to harness human genes. “Since mouse T cells are not very representative of human responses, this model is the best way to predict this therapy’s promise for human cancer treatments.”
Comparing the performance of the hydrogel to subcutaneous (SC) saline administration and IV control treatments – which were able to cure 10% and 40% of treated animals – the researchers found that the PNP-1-5 hydrogel could cure 70% of the treated animals. When experimental variables, such as the mice’s original tumor size were considered, the data showed that delivery of the PNP-1-5 hydrogel resulted in a statistically significant faster time-to-cure compared to SC saline or IV controls. When CAR T cell dosing at concentrations of four folds higher was administered via SC or IV, the cure rate was still slower than CAR T-cell therapy delivered via the hydrogel.
Adding the cytokine IL-15 to the gel further enhanced the treatment response, with all experimental animals presenting as cancer-free after 12 days.
A more efficient approach to CAR-T cell therapy
“In our study, we found that far fewer CAR T cells are required for effective treatment when they are delivered in our PNP hydrogels,” says Appel.
“These hydrogels are acting as little CAR T factories within the body to expand and activate the cells. This means that less time, money and resources are needed for expanding the patients T cells outside of the body prior to treatment. Expediting this expansion process has the potential to save the lives of cancer patients who are eagerly waiting for treatment,” adds Grosskopf.
Some polymers can instigate immune responses, but not PNP – a further advantage of the team’s approach, says Grosskopf: “Our PNP hydrogels have demonstrated negligible immune responses (they are basically invisible to the body!) and biodegrade over time once injected.”
The next step for the Appel lab will be to continue preclinical studies using larger, more complex models that represent different tumor types. “We are trying to design more studies to better understand how the patient’s immune system engages with our injectable CAR T factories, while also evaluating how best to expand and activate the CAR T cells in these materials,” Appel says.
“We hope to see this therapy moving toward the clinic over the next couple of years,” Grosskopf concludes.
Dr. Eric Appel and Abigail Grosskopf were speaking to Molly Campbell, Senior Science Writer for Technology Networks.
Reference: Grosskopf A, Labanieh L, Klysz et al. Delivery of CAR-T cells in a transient injectable stimulatory hydrogel niche improves treatment of solid tumors. 2022. Sci Adv. doi: 10.1126/sciadv.abn8264.
