Engineered chimeric antigen receptor (CAR)-T cell delivery is the methodology by which clinicians introduce the cancer-targeting therapeutic system of the CAR-T cell to the human body. CAR-T cells, which utilizes genetic modification of human T-cells to contain antigen binding sequences in addition to the receptor systems CD4 or CD8, are useful in direct targeting and elimination of cancer cells through cytotoxicity.
CAR-T cell delivery involves many varying modalities for implementation, spurring innovative biomedical research to address these modalities. These delivery mechanisms serve to address the limitations of CAR-T cells in translational experimentation and clinical trials, including shelf-life, off-target effects, and tumor infiltration.[1] As of April 2023, six CAR-T cell therapies are clinically approved by the FDA, all of which target hematologic (blood-based) cancers, including multiple myeloma and B-cell leukemias.[2][3] Novel engineered compound-based delivery methods, some of which are in clinical trials, aim to address limitations related to CAR-T cell delivery with the focus to target non-blood based cancers.[4][5]
Systemic and intravenous delivery
The classic method of administration of CAR-T cells to cancers within the human body is through intravenous (IV) central line infusion.[6] This infusion allows the CAR-T cells to enter the body’s cardiovascular system, entering the circulation (systemically) amongst developing hematologic cancers. This facilitates the final step in generation and implementation of both autologous and allogeneic CAR-T cell therapy. While this delivery method is reliable for hematologic cancers, as demonstrated by successful clinical trials and FDA regulation, systemic delivery may result in an increase in autoimmune overload, leading to toxic disorders such as cytokine release syndrome (CRS).[1] Discrimination between healthy and malignant cancer cells may additionally result in aplasia, or extremely low or absent amounts of healthy blood cells.[7] Thus, clinically recommended dosage amounts are in place for current CAR-T cell therapies.[8][9][10][11][12][13][14] Current methods exploring ways to improve such complications have been introduced recently by researchers, including “off-switches” to turn off CAR-T cells after initial therapies and further genetic modification to avoid immune rejection.[1][7][15][16] While systemic delivery is important for targeting hematologic cancers, it remains inefficient at targeting solid, or non-circulatory, cancerous tumors. Therefore, regional, or localized targeting strategies utilizing CAR-T cells have arisen in pre-clinical research.[4][5][17][18][19]
Localized delivery mechanisms
Solid tumors, which typically take the form of neoplasms in epithelial cells or in bones, tissue, or adipose (fat), are different than hematologic cancers in that they form a mass of cells, thereby maintaining multiple layers of protection.[20] Because CAR-T cells attack cancerous cells at a surface level, this leaves the CAR-T cells vulnerable to cancerous cell resistance, which renders the CAR-T cell inefficient.[21][22] In recent years, cellular and genetic engineering methods have been explored by researchers to overcome layered protection of solid tumors, in addition to other challenges that have been presented in the advent of CAR-T cell delivery such as in-situ editing and manufacturing, negative immune responses, and biocompatibility of delivery structures.[4][5][17][23][24][25][26] Some of the methodologies used to suspend and deliver CAR-T cells include hydrogel and polymeric gel-based delivery systems, thin polymeric films, and microneedle patches. Most of these devices, currently still in the pre-clinical phase, are intended to be injected or surgically inserted directly into the solid tumor mass. While initial clinical trials have been unsuccessful due to relatively inefficient delivery as compared to direct injection and high immunosuppression, recent research has shown promise in overcoming these barriers.[4]
Gel-based delivery
Gel-based delivery of CAR-T cells involves implantation or injection of a hydrogel or polymer gel into the target solid tumor. These gels suspend CAR-T cells in various ways through manipulation of cell-specific chemistry or by fixing the cells in a polymeric matrix. One strength of gel-based delivery is that these systems are functionally biodegradable, so once the CAR-T cells have been administered, the depot does not stay in the body, reducing immunosuppressive conditions or tumor resistance.[24][27]