One type of immunotherapy known as adoptive cell transfer (ACT) involves the adding specialized immune cells into a patient’s body. The ACT process improves cytotoxic T lymphocytes (CTLs), immune cells responsible for killing foreign cancer cells. A patient undergoing ACT will provide blood or tissue from which doctors extract immune cells. Then, technicians will grow and modify the immune cells in a specialized laboratory, producing an ample supply of CTLs engineered to locate and kill the patient’s tumor cells. Doctors will then infuse the new and improved CTLs back into the patient. When successful, these specialized cells will quickly and efficiently eliminate the cancer cells.
Last week, Nature Medicine published promising interim results from a phase 2 clinical trial evaluating an ACT regiment for the treatment of metastatic colorectal cancer (CRC). The therapy tested involves CTLs specially designed to recognize a “neoantigen,” a protein specific to tumor DNA. When the immune system recognizes these proteins as foreign, it can initiate an anti-tumor immune response against cells which express neoantigen. Because of the specificity of neoantigens to tumors and not healthy cells, targeting these proteins can help concentrate treatment on cancer cells.
To produce the ACT product for the clinical trial (NCT03412877), researchers isolated the T cell receptors (TCRs) from the immune cells of patients with metastatic CRC. They then took two components of the TCR, the α and β chains, and incorporated them into a vector, carriers used to deliver genetic material into a cell. Next, the technicians add the vector containing the α and β chains of the TCR to immune cells harvested from the patient. The cell product, described as “neoantigen reactive TCR-transduced T cells,” is expanded and returned to the patient.
Seven patients with advanced metastatic CRC, whose disease had regressed following several other treatments, received the ACT regimen. Three patients achieved a clinical response characterized by temporarily regressed metastatic disease. In these patients, reduced metastasis to the liver, lungs, and lymph nodes occurred for between four and seven months.
One month after ACT, at least 10% of the T cells circulating in the blood of the responding patients were the TCR-transduced cells. Two additional patients who did not achieve an objective response also expressed similar levels of TRC-transduced cells. Notably, TCR-transduced T cells still comprised about 20% of the circulating T cells in one of the responding patients.
The study confirms the regimen's safety by showing that cancer patients can tolerate ACT with T cells modified to express personalized neoantigen-reactive TCRs. This reassures us that the treatment is well-tolerated and safe for patients. Further, this treatment has efficacy in some patients with metastatic CRC that has not responded to other therapies.
Sources: Nat Med