Adoptive Cell Therapy (ACT) is a cancer treatment that harnesses the patient’s own immune system. This immunotherapy approach utilizes immune cells, most often T-lymphocytes, to seek out and destroy malignant cells throughout the body. ACT is considered a living treatment because the modified cells can expand and persist within the patient, offering the potential for long-term surveillance against cancer. The core concept involves isolating these specialized immune cells, enhancing their cancer-fighting capabilities outside the body, and then reintroducing them to the patient.
How Adoptive Cell Therapy Works
ACT begins with collecting the patient’s immune cells, usually through leukapheresis. This procedure involves withdrawing blood, separating the white blood cells containing T-lymphocytes, and returning the remaining blood components to the patient. Alternatively, for certain ACT types, the source material is a surgical sample of the tumor itself, which contains T-cells that have naturally infiltrated the cancerous tissue.
Once harvested, the T-cells are transported to a specialized laboratory for processing and expansion. This ex vivo step involves either genetic modification or simple activation and culturing to increase the cell population. The cells are stimulated to multiply, often resulting in billions of cancer-specific T-cells ready for reinfusion. This manufacturing step can take several weeks, sometimes requiring the patient to receive bridging therapy.
Before administration, patients typically receive a short course of lymphodepleting chemotherapy. This preparatory chemotherapy reduces the patient’s existing immune cells, eliminating competition for growth factors. It also creates space for the newly introduced therapeutic T-cells to expand and persist effectively. Finally, the engineered or expanded T-cells are infused back into the patient, usually intravenously, where they target and eradicate tumor cells.
Key Differences in Adoptive Cell Therapies
Chimeric Antigen Receptor (CAR) T-cell Therapy
CAR T-cell therapy involves genetically engineering T-cells with a synthetic receptor. This Chimeric Antigen Receptor allows the T-cell to recognize a specific antigen, such as CD19 on B-cell malignancies, directly on the surface of the cancer cell. This targeting is MHC-independent, meaning it does not rely on the body’s major histocompatibility complex presentation. This independence allows CAR T-cells to overcome certain tumor escape mechanisms.
Tumor-Infiltrating Lymphocyte (TIL) Therapy
TIL therapy uses T-cells that have already migrated into the tumor microenvironment. These cells are isolated from a surgically removed tumor sample and expanded in vitro without genetic modification. TILs naturally recognize a wider array of tumor antigens, reflecting the diversity of the cancer cells. This makes TIL therapy a promising strategy, particularly for solid tumors.
T-cell Receptor (TCR) Therapy
TCR therapy modifies T-cells to express a new, high-affinity T-cell receptor. Unlike CAR T-cells, this approach remains MHC-dependent, requiring the antigen to be presented by the MHC molecule on the tumor cell surface. The benefit of TCR therapy is its ability to target intracellular tumor proteins, which are far more numerous than surface antigens. This makes it useful for solid tumors that lack suitable surface targets.
Managing Potential Treatment Side Effects
Cytokine Release Syndrome (CRS)
The activation and proliferation of infused T-cells can lead to significant systemic inflammation, resulting in Cytokine Release Syndrome (CRS). CRS occurs when activated T-cells release a massive amount of inflammatory signaling molecules, called cytokines, into the bloodstream while killing cancer cells. Symptoms range from high fever and fatigue to severe complications like hypotension and organ dysfunction.
The primary intervention for managing moderate to severe CRS is the drug tocilizumab, an antibody that blocks the receptor for the inflammatory cytokine Interleukin-6 (IL-6). This targeted blockade interrupts the inflammatory cascade and reverses symptoms. Corticosteroids are also used to suppress the immune response, especially in cases that do not respond sufficiently to tocilizumab.
Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)
ICANS is a second serious complication presenting as a range of neurological symptoms. ICANS typically manifests a few days after CRS onset and can include confusion, language difficulties, and seizures. Tocilizumab is limited in treating ICANS because it does not easily cross the blood-brain barrier. The standard treatment for ICANS is immediate administration of corticosteroids, which reduce neuroinflammation.
Current Successes and Research Directions
ACT has demonstrated success in treating hematologic malignancies, such as certain B-cell acute lymphoblastic leukemias and non-Hodgkin lymphomas. CAR T-cells targeting the CD19 protein have achieved high rates of complete remission in patients whose disease was refractory to conventional therapies. This success in liquid tumors has changed the treatment landscape for advanced blood cancers.
The greatest challenge is translating this efficacy to solid tumors, which represent the majority of cancer cases. Solid tumors pose multiple barriers, including physical structures that impede T-cell penetration and an immunosuppressive microenvironment that deactivates therapeutic cells. Research focuses on engineering T-cells to overcome this hostile environment by increasing their persistence and resistance to suppression.
A major logistical hurdle is the reliance on patient-derived (autologous) cells, which requires a custom manufacturing process for every individual. Researchers are developing “off-the-shelf” or allogeneic therapies using T-cells from healthy donors that can be manufactured in advance. The technology is also being explored beyond oncology, with studies investigating engineered T-cells to treat chronic infectious diseases and severe autoimmune disorders.