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What Is Adoptive Cellular Immunotherapy?
Adoptive cellular immunotherapy is a medical procedure that uses the patient’s immune cells to target and destroy cancer or other disease-causing cells. The idea of adoptive immunotherapy originated in the 1980s, when researchers discovered T cells could recognize and eliminate cancer cells. However, it wasn’t until the 1990s that significant progress was made in laboratory techniques necessary for the proliferation of T cells ex vivo, or outside of the body.
In the years since, adoptive T-cell therapy has emerged as a promising treatment for several types of cancer, cardiometabolic disorders, fibrosis, and other autoimmune diseases. Advancements in the genetic modification of harvested immune cells continue to produce safer, more effective treatments, such as engineered TCR, CAR-T, and NK cell immunotherapies.
How to Perform Adoptive T-Cell Transfer
Adoptive immunotherapy involves removing immune cells—often T cells—from the patient’s blood or tumor site and sending the gathered cells to a laboratory for processing. In several types of adoptive T-cell therapy for cancer, the original immune cells are genetically altered to express new or enhanced receptors on their membranes to better target and survive the tumor microenvironment.
The cells are then activated with bioreagents and induced to grow in the laboratory. This cell culture replicates multiple times, exponentially increasing the number of specific cancer-targeting immune cells during a process called expansion.
These enriched immune cells are then re-infused back into the patient’s body. The patient is closely monitored for side effects to quickly address dangerous overactive immune responses, such as cytokine release syndrome.
Types of Adoptive Cell Therapy
There are several types of adoptive immunotherapy that fall into four main categories:
- Tumor-infiltrating lymphocyte therapy
- Engineered T-cell receptor therapy
- Chimeric antigen receptor T-cell therapy
- Natural killer cell therapy
Tumor-Infiltrating Lymphocyte (TIL) Therapy
Tumor-infiltrating lymphocyte therapy uses T cells specifically harvested from the patient’s tumor site as the basis for treatment. The procedure typically involves removing a small piece of the patient’s tumor and sending it to a lab where T cells that have already infiltrated the tumor are isolated.
This T cell population inherently has a higher concentration of tumor-infiltrating lymphocytes (TILs) with receptors specific to targeting the patient’s cancer. The TILs are activated, expanded, and infused back into the patient, enriching the number of immune cells best equipped to neutralize the cancerous cells.
TIL therapy is a relatively straightforward adoptive cell therapy technique. It does not involve genetically altering the harvested cells while maintaining the reduced risk of rejection by using the patient’s own cells. However, not all patients have sufficient T cells infiltrating their tumors to perform TIL therapy. This technique also lacks the enhanced tumor targeting and neutralizing capabilities of therapies using artificially engineered receptors.
Engineered T-Cell Receptor (TCR) Therapy
Engineered T-cell receptor (TCR) therapy modifies a patient’s T cells to target and neutralize cancer cells. This is done by genetically engineering the harvested T cells to express specific TCRs that recognize tumor-associated antigens. TCR therapy can target a broader range of cancers than TIL therapy, including non-tumor blood cancers.
However, TCR therapy is MHC dependent, requiring the engineered TCR to bind to antigen-presenting major histocompatibility complex (MHC) on the membrane of cancer cells. While this induces a more potent immune response than relying on the original immune response alone, it may risk strong binding to off-target cells. This increases the risk of acute toxicity and overactive immune side effects and must be closely monitored.
Chimeric Antigen Receptor (CAR) T-Cell Therapy
Similar to TCR therapy, CAR T-cell therapy genetically modifies a patient’s T cells to express novel receptors designed to target cancer cells. However, these chimeric antigen receptors can be engineered to directly bind antigens that are highly specific to the target cell and not dependent on MHC binding. This greatly reduces the potential for off-target side effects seen in TCR therapy.
Engineering effective CAR-T therapies require extensive study and knowledge of specific cancers or diseases, which limits the range of treatments available to patients. CAR-T therapy is also labor-intensive compared to other non-personalized treatments, such as chemotherapy. However, once thoroughly vetted and implemented, CAR T-cell therapy has been remarkably successful in treating certain types of cancer.
CAR-T therapies are currently approved by the Food and Drug Administration to target CD19 (a receptor found on the surface of most B cells that determines growth and development activity; often expressed by leukemia, lymphoma, and myeloma cells) and BCMA (an important signaling receptor found on mature B cells; often expressed by lymphoma and myeloma cells). The two major drawbacks of CAR-T therapy are the high cost of development and treatment compared to other adoptive cell therapies and the potential to cause severe adverse immune reactions, such as cytokine release syndrome (CRS).
Natural Killer (NK) Cell Therapy
Natural killer cells are another type of white blood cell with a critical role in the body’s immune response to cancer and other diseases. In contrast to T cells, NK cells do not require specific antigens to recognize and attack cancer cells. These innate immune cells target cells that lack normal surface proteins, a frequent occurrence in cancer cells.
Like T-cell therapy, adoptive NK-cell therapy may be administered by expanding and activating a patient’s own NK cells. However, NK cell therapies may also be derived by allogeneic means, taken from a human donor other than the patient without causing the same immune rejection that non-self T cells would. This creates the ability to have a therapeutic donor pool of NK cells, making NK therapies an attractive option. Once donor cells are collected, clinical researchers may simply enrich the NK cell concentration or involve the genetic alteration of NK cells to enhance their antidisease properties, including CAR-NK therapy.
NK-cell therapy benefits from the NK cell’s innate ability to neutralize diseased cells and has shown fewer side effects related to rejection by the host’s immune system. However, NK-cell therapy has limited persistence once reintroduced into the body due to the lack of cytokine-signaling support, as seen in T-cell therapies. Further study may lead to enhanced CAR-NK techniques that include the addition of strategic cytokine receptors in engineered NK cells.
Risks of Adoptive T-Cell Therapy
The greatest clinical risk of adoptive T-cell therapy remains the potential to induce dangerous overactive immune responses. If not immediately addressed, cytokine release syndrome and neurotoxicity can occur, leading to uncontrolled fever, confusion, seizures, and organ damage.
Many such side effects can be mitigated with prompt medical attention and a strategic mix of immunosuppressants. However, scientists continue to develop novel CARs and therapy administration strategies to prevent undesired immune reactions while keeping the targeted therapy effective.
Cellular Therapies for Cancer
Surgery, radiation therapy, chemotherapy, and hormone therapy have long been the standard treatment options for cancer patients. These treatments are fast to implement and relatively cheap to administer, but they are also nonspecific and damage large numbers of healthy cells. In addition, if the cancer is not fully removed or destroyed, the patient can relapse and their cancer may metastasize.
Alternatively, adoptive cellular therapies are highly targeted and can be tailored to the specific patient’s cancer. While they do suffer from adverse autoimmune reactions, such as CRS, they have fewer non-specific toxic side effects than traditional treatments like radiation and chemotherapy. In addition, many adoptive therapies are long-lasting, continuing to target cancer cells even after treatment is complete. Especially when combined with other cancer treatments, cellular therapies have the potential to cure many types of cancer.
Nanotein’s Ex Vivo CAR-T Cell Expansion Technology
Obtaining sufficient immune cells from a patient for adoptive cell therapy can be challenging. Both the number of cells and their maturity stage are important for clinical treatment success. To this end, the activation and expansion steps in all adoptive immune cell therapies are critical.
Traditional methods of activation and expansion are inefficient, non-specific, and introduce clinical risk by using synthetic contaminants. To address this, Nanotein Technologies developed novel protein-based T cell and CAR-T technology that requires less time and fewer T cells while improving clinical outcomes.
Nanotein’s NanoSpark STEM-T Soluble T Cell Activator focuses on TSCM CAR-T expansion, generating large quantities of clinically potent T cells in a less differentiated state for increased self-renewal ex vivo and clinical safety during treatment.
Contact us today to learn more.
