Teaching the body to fight tumors using cancer immunotherapy

Selected as the 2013 “Breakthrough of the Year” by Science magazine, cancer immunotherapy shows a completely new way to treat malignancies by using the body’s own immune system, and not by targeting the tumor itself. This cutting-edge area of research and therapy has shown very promising results. However, further investigation is needed to turn immunotherapy into a cancer therapy that can be broadly applied.

Stimulating the immune system to battle tumors is the scope of cancer immunotherapy. “Cancer immunotherapy serves a dual purpose,” explains Prof. Dr. med. Thomas Wölfel from Internal Medicine III of the University Medical Center Mainz. “On the one hand, we try to release the existing immune responses, using for example, checkpoint inhibitors or antigen-based cancer vaccines that do not target the tumor itself, but take away immunological barriers. On the other hand, we want to give patients the effectors they lack as antibodies, or T cells that specifically target cancer cells.”

Cancer immunotherapy: a fragile balance between fighting cancer and preventing autoimmunity

Checkpoint inhibitors: releasing the brakes on T cells

The balance between stimulatory and inhibitory signals is crucial for avoiding uncontrolled immune reactions that would damage the body. Therefore, immune cells have immune checkpoints on their surface. Those receptors – when binding to the ubiquitous ligands on body cells – prevent them from attacking “normal” cells. Tumors can also activate suppressive immune checkpoint pathways that minimize the immune response. In the late 1990, James Allison, a cancer immunologist at the University of Berkeley in California, found that the administration of antibodies at one of these checkpoints, the cytotoxic T-lymphocyte associated protein 4 (CTLA-4), eliminated tumors in mice (Leach DR et al., 1996).

Cancer vaccines: stimulating the immune system to destroy cancer cells

Another approach that targets the early steps in the cancer-immunity cycle is the vaccination with tumor-associated or tumor-specific antigens. The purpose of cancer vaccines is to initiate and boost an antigen-specific T cell response when the tumor has failed to do this. Advances in technology have led to the identification of many antigens that can be targeted in cancer immunotherapy. These antigens are introduced into the patients, where they stimulate effector T cells to selectively attack cancer cells that express them. There are several ways to vaccinate the patients. Dendritic-cell vaccines are considered among the most successful approaches so far, as these cells can elicit strong immune responses (see text box). Other vaccination approaches use whole tumor cells, DNA or RNA, peptides or proteins, as well as viruses (Kamta, et al., 2017). “There is a high interest in finding neoantigens, which arise from mutations within the cancer genome, and which can elicit a T cell response,” remarks Wölfel. “In recent years, new high throughput DNA-sequencing methods have allowed the identification of antigens in individual patients in an acceptable period of time. Nevertheless, the mean time of approximately three months might be too long for some patients in an advanced stage of the disease without other therapeutic options.” Despite researchers’ high expectations, early clinical studies of vaccines did not show the anticipated results, as cancer-mediated T cell suppression prevented T cell activation. Therefore, recent studies have actively focused on combining vaccination with other approaches such as T cell checkpoint inhibition (Patel et al., 2016). Improving vaccine design, and using vaccines to increase the effects of standard therapies could also maximize therapeutic benefits for cancer patients. [info_box headline="Dendritic cell based vaccines"] Dendritic cells (DCs) are the most powerful antigen-presenting cells in the human body. They take up foreign molecules, process them and present them to T cells starting an immune response. During the past decade, DCs have been the subject of numerous studies aimed at gaining a better insight into their immunobiology, their interaction with both the innate and adaptive immune system, and their role in the tumor microenvironment. In the context of cancer immunity, DCs can activate tumor-specific T cells in lymphatic tissues. This is why DCs can be used as adjuvants for vaccination, and why they hold great promise for the treatment of cancer (Shang, et al., 2017). Sipuleucel-T is so far the only FDA-approved DC-based vaccine. It is used for treating advanced prostate cancer, as it has shown a survival benefit for patients. “Dendritic cells are essential for inducing an immune reaction,” explains Prof. Dr. med. Thomas Wölfel from Internal Medicine III of the University Medical Center Mainz. “The question is how they should be used therapeutically. Should they be extracted from the body, loaded with the relevant antigen and then reinfused, or should they be activated in the body through so-called danger signals?” Formulated in 1994 by Polly Matzinger, the danger model postulates that the immune system differentiates between “dangerous” and “safe” by recognizing alarm signals coming from injured tissues. These danger signals can activate DCs and initiate an immune response. If tumors do not send those signals, they remain invisible to the immune system. For this reason, the efficacy of DC vaccines is strongly influenced by the method of administration. Low numbers of DCs at the tumor site, impaired DC maturation, or the presence of inhibitory signals can endanger the therapeutic efficacy of the vaccine. Ex vivo DCs are mainly generated from bone marrow progenitor cells in the presence of GM-CSF and IL-4 or IL-13 (Pizzurro et al., 2015). In vivo vaccination strategies, where DCs are directly activated at multiple sites, offer a cheaper and simpler approach. To optimize DC-based vaccination strategies, researchers are now focusing on determining the optimal tumor-associated antigens to be used, the best way of administration, as well as possible combination therapies.[/info_box]

Cell therapy: providing the immune system with the missing effectors

The aim of immune checkpoint inhibitors and cancer vaccines is to trigger pre-existing immune responses. Yet what happens if there are no or not enough effector cells to fight the tumor? To overcome this deficit, researchers can extract T cells from a patient’s blood or tumor samples, expand them in vitro, and reintroduce them into the patient as a cancer therapy. Steven Rosenberg had been working for years on the adoptive transfer of tumor infiltrating lymphocytes (TILs), when in 2010, he published encouraging results obtained with the so-called chimeric antigen receptor therapy (CAR). Here, a patient’s T cells are collected and genetically engineered so that they target cancer cells (June et al., 2018). CAR therapy holds significant promise for the future. Although first used in hematological malignancies, recent studies have shown that adoptive cell transfer can also be used to treat other malignancies. The biggest challenge remains toxicity, which sometimes results in life-threatening immune reactions, as the infusion of billions of lymphocytes into the patient can trigger the release of cytokines. These mediators can cause fever, fatigue, cardiac, liver, and renal toxicity, and eventually organ failure. Genetic engineering could allow the use of TILs that have been sensitized to tumor-specific antigens, which would make the adoptive transfer safer and more effective. “The aim is transferring effectors with known specificity, but this is complex and still very expensive,” explains Wölfel. To improve efficacy, CAR therapy could also be combined with checkpoint inhibition, as the transferred T cells have to overcome the barriers set by the cancer cells as well.

Future challenges: finding the right approach for each patient

At the end of the 19th century, a bone surgeon named William B. Coley set the cornerstone for the immunotherapy of cancer. Coley had heard of several reports of patients who had been cured of inoperable tumors after developing erysipelas, a potentially fatal infection caused by Streptococcus bacteria. Believing in the potential curative effects of these bacteria for cancer, in May 1891, he injected toxic bacteria into the neck of a drug addict named Zola, who could not eat anything because of a tumor obstructing his throat. After repeated injections over five months, the tumor began to shrink, and finally disappeared. Zola had contracted erysipelas, and the inflammation had spurred his immune system to fight the cancer cells. Coley dedicated his life to optimizing his approach, and to defending his reputation from numerous detractors. He treated nearly 1,000 patients, and published more than 100 papers on the subject. Yet he could not explain why his treatment worked. Only recently could immunologists confirm that the immune system can recognize and attack cancer cells.