The Immune system
Our Immune system comprises different cell types, which are programmed to identify and destroy foreign cells. There are three main categories of cells in our immune system: (1) Lymphocytes comprising the T and B cells, (2) Antigen-presenting cells: macrophages and dendritic cells (3) Granulocytes: neutrophils, eosinophils, and basophils. The immune response generated by these cell types can be classified in to two types: the innate immune response and adaptive immune response.
The innate immune response is the first line of defense consisting of the granulocytes, the macrophages, and the dendritic cells. The adaptive immune response starts later when the antigen-presenting cells capture the foreign antigen and present it to the appropriate T or B cells. The T cells eliminate the foreign antigens by inducing a cytotoxic T lymphocyte (or CTL) response and the B cells generate antibodies which destroy the cells carrying the foreign antigens.
How tumor cells evade the immune system
An important function of the immune system is to distinguish between the self/host and foreign cells. To achieve this, the cells of the immune system use certain checkpoints. The checkpoints are molecules/signaling pathways which are either activated or inactivated to initiate an immune response. The checkpoints are also responsible for preventing attacks on self or healthy cells and averting an autoimmune response (Immune response generated against the host’s natural healthy cells). Tumor cells over-express these checkpoint molecules. The immune system fails to recognize the tumor cells with checkpoint molecules on their surface as foreign cells. Thus, the tumor cells evade the immune response and continue to proliferate.
The tumor cells also thrive in a unique microenvironment which helps them to evade the immune checkpoints and suppress immune responses. The tumor cells can influence the surrounding cells in the microenvironment to secrete substances that prevent CTL responses by the T cells.
History and Concept of Immunotherapy
The concept of immunotherapy was first developed by William B. Coley in 1891. One of his initial patients was a 17-year-old girl diagnosed with a malignant bone tumor. Despite stringent treatment regimens, including amputation of the forearm, she died of tumor metastasis. After losing the 17-year-old girl to cancer, Coley was determined to find a cure for the disease. He did an extensive literature search and came across a case of inoperable malignant neck tumor, which disappeared after the patient developed a bacterial infection – erysipelas. Eventually, Coley found about 47 documented cases of cancer remission due to bacterial infections. Based on the literature evidence, Coley was convinced that bacterial infections could shrink the tumor. In 1891, he injected his first cancer patient with streptococci. Coley hypothesized that the infection generated by the streptococci will lead to tumor shrinkage, which turned out to be the case. Since the live bacterial cultures can be detrimental, Coley developed a mixture of heat-killed streptococci and other bacteria which were referred to as Coley’s toxin. Over the next 40 years, Coley injected more than 1000 patients with this mixture and was known as the “Father of Immunotherapy”. Coley’s instinct that stimulating an immune response is beneficial in targeting the tumor cells was right on target. Studies demonstrating reduced tumor progression in patients with infections or increased neutrophil numbers further reiterate the role of the immune system in preventing tumor progression.
Despite the success and novelty of the concept, Coley’s work was criticized for lack of consistency. Coley failed to document follow-up appointments with patients who responded successfully to immunotherapy. There were no standard protocols for the toxin preparation and more than one route was used for toxin administration. Because of these inconsistencies, several doctors had trouble repeating Coley’s results, and the advent of chemotherapy/radiation replaced the interest in Coley’s toxins and immunotherapy.
An interest in immunotherapy was triggered again in the 90’s when several studies showed that dendritic cells (antigen-presenting cells which process the antigens and present them to T cells and activate them to generate a CTL response) are capable of identifying, processing, and presenting tumor antigens to T cells, which in turn destroy the tumor cells by generating a CTL response. Currently, numerous studies and clinical trials are being conducted to develop cancer immunotherapy drugs.
Future of cancer immunotherapy
Recently, President Obama introduced the Precision Medicine Initiative. The idea behind the policy is to customize treatment options on an individual basis instead of the one-size-fits-all policy. The policy aims to take into consideration specific environmental, genetic, and life-style factors before coming up with a treatment plan especially in cancer patients who fail to respond to the standard therapy. The policy will aid immensely in developing immunotherapy drugs for individual cancer patients by utilizing the patient’s own immune cells. Some of the immunotherapy drugs that are currently in clinical trials are the immune checkpoint inhibitors and cancer vaccines.
Development of Immune checkpoint inhibitors: The immune system has checkpoints in place to prevent attacks on healthy cells. The cancer cells use these checkpoints and escape the immune surveillance. Using specific checkpoint inhibitors will help the immune system to recognize the tumor cells and destroy them.
PD-1 and PD-L1-(Programmed death ligand 1) – This is a checkpoint protein on T cells, which acts as an off switch and prevents immune responses against normal host cells. The tumor cells have increased amounts of the PD-1 protein which helps them to escape the immune system. Immunotherapy drugs like Pembrolizumab target the PD-1/PDL-1 and unmask the cancer cells which are then destroyed by the immune system.
Development of Cancer Vaccines: Dendritic cell vaccines are the most successful form of vaccines currently being used to treat some forms of prostate cancer. These are autologous vaccines which are prepared from the patient’s own immune cells. Cancer cells have specific antigens on their surface, processing these antigens and vaccinating individuals with the antigen preparation will induce an immune response that recognizes the cancer antigens and destroys the cells carrying the antigen. Sipuleucel-T is a cancer vaccine given to men with metastatic prostate cancer (cancer spreads from the prostate to other parts of the body). These vaccines are customized to each individual using their white blood cells, which are modified to carry the cancer antigen and initiate the immune response.
For several decades cancer patients have been treated with the conventional methods involving surgery, radiation, and chemotherapy. Unlike these standard treatment options, immunotherapy may take some time to show effect because it operates on activating a plethora of cells in the immune system rather than targeting individual cancer cells. However, once the immune response is generated against the cancer cells, the effect is long lasting. Cancer immunotherapy is a less invasive, long-lasting, and represents the future of cancer treatments.
Editor: Hanaa Hariri