Cancer Immunotherapy: Tumor-Infiltrating Lymphocytes
Boosting Activated T-Cell Responses
As we’ve discussed in the past two articles, though the immune system is extremely versatile and powerful, in some individuals, cancer cells are able to develop mechanisms to avoid or even directly block the immune system, allowing them to form life-threatening tumors.
Now, one way to overcome these mechanisms is with the help of drugs like the immune checkpoint inhibitors we focused on in the previous article. But, another class of immunotherapy are adoptive cellular therapies (ACT), which, on a fundamental level, isolate and extract T-cells, expand their populations outside of the body, and then inject them back into the patient. Two examples of ACTs include: CAR-T cell therapy, which I will cover in a future article, and the focus of this article: tumor-infiltrating lymphocyte (TIL) therapy.
Note: This is part 3 of my article series on cancer immunotherapy and covers the basics of tumor infiltrating lymphocytes. Understanding it does require some understanding of the cellular mechanisms of our immune system. Also I may refer to immune checkpoint blockade therapies a couple times during the article.
If you don’t have prior exposure or understanding of how the immune system works or what immune checkpoint blockade therapies are, check out parts 1 and 2 in the series, respectively, and then come back to continue reading this article!
Tumor Immune Microenvironment
The tumor microenvironment (TME) consists of a variety of different components, including the cancer cells, blood and lymph vessels supplying the tumor, and of note, tumor infiltrating immune cells and cytokines and chemokines that regulate immune responses. These immune cells make up the tumor immune microenvironment (TIME), and include myeloid-derived suppressor cells (MDSC), tumor-associated macrophages (TAM) and cytotoxic lymphocytes. Studies show that increased MDSC & TAM density in the TME can actually help the tumor grow, while increased numbers of cytotoxic lymphocytes can help fight the tumor and promote recovery.
The nature of a specific patient’s TIME plays a huge role in how they respond to different cancer therapies, especially when it comes to immunotherapies. As such, there are different classifications for TIMEs that can allow researchers and oncologists to develop an accurate prognosis and predict how effective different therapies might be. On a basic level, these classifications range from “hot” to “cold”.
“Cold” tumors are those that haven’t been infiltrated by T-cells. These tumors often respond poorly to immunotherapies, and thus, are usually treated with more traditional therapies like chemotherapy and radiation therapy. Though the nature of the TIME varies from patient to patient, cancer types classified as being immunologically cold include many breast cancers, ovarian cancer, prostate cancer, pancreatic cancer, and glioblastomas.
On the other hand, “hot” tumors show signs of inflammation, which suggests that T-cells have already infiltrated the tumor, recognized the cancer antigens, and begun attacking the tumor. These tumors usually respond much better to immunotherapies like the immune checkpoint blockade therapy. Only a few cancer types are generally considered “hot”, including melanoma, bladder, kidney, head and neck, and non-small cell lung cancer.
Taking Advantage of Tumor Invading Lymphocytes
TIL therapy, developed by Dr. Steven Rosenberg at the National Cancer Institute (NCI), takes advantage of TIMEs that possess some T-cells that have infiltrated and begun attacking the tumor. Oncologists perform a biopsy of the of the patient’s tumor to obtain these TILs along with tumor cells.
“Intuitively, what better place to find T cells that are reacting against the cancer than in the stroma of the cancer itself?”
— Dr. Steven Rosenberg
From the biopsy, the DNA of tumor cells is analyzed to identify antigens that are mutated (neoantigens) enough such that the immune system can target these antigens without also attacking normal body cells expressing those antigens. From this, the epitopes, which are the specific parts of the neoantigens that can be recognized by the immune system are designed and inserted into dendritic cells also extracted from your body.
These engineered dendritic cells are then cultured alongside the TILs extracted from the biopsy. This not only helps the TILs develop stronger affinity for their target antigens, but also allows some of them to develop receptors for the designed epitopes that may make the anti-tumor response more effective and specific.
Finally, these cultured T-cells are assayed to test for cytokines like interferon-gamma, which is associated with tumor clearance to ensure that they respond to the antigens they have been trained on. T-cells that can recognize the mutated neoantigens are selected, induced to undergo clonal expansion, and then transfused into the patient. Once in the body, the large populations of transfused T-cells can get to work at attacking the tumor.
In this way, TIL therapy uses a person’s T lymphocytes that already recognize and attack the tumor as a treatment for the cancer.
Impact of TIL Therapy
So far, TIL therapy has been effective against a few cancers, including melanoma, colorectal cancer, bile duct cancer, and breast cancer. In the case of melanoma, TIL therapy achieved objective response rates (ORR), a measure of the proportion of patients that show a partial or complete response to therapy, of 40–50%, with 10%-20% of patients demonstrating a complete response, often lasting for 3–5 years.
“It’s somewhat ironic that the very mutations that cause a certain cancer may turn out to be its Achilles’ heel and enable immunotherapy treatment.”
— Dr. Steven Rosenberg
However, TIL therapy is yet to be commercialized because the procedure is long and expensive to perform. However, innovations continue to occur, mainly focusing on reducing the time required to produce the T-cells. For example, Iovance Biotherapeutic developed a new process that takes just 16 days to produce the T-cells.
Another challenge is the fact that the therapy is ineffective in cold tumors that lack sufficient numbers of active TILs, or tumors with strong immunosuppressive mechanisms in place that can prevent the action of the manufactured T-cells.
Research into this therapy is progressing very quickly, and work-arounds for these challenges could be developed in the coming decades, which could save millions of lives every single year. And even if TIL therapy itself is unable to overcome these limitations, the lessons learned from this research are bound to applicable to other therapies or even allow the development of new therapies against cancer. So, regardless of how the research into this therapy progresses, there is no doubt that it is an important innovation in the field of cancer immunotherapy.
