"Walk down isle 4, take a box of Immutrap pills and use it once a week for a month. You'll fully recover in no time." When do you think we will hear these words for real when we are diagnosed with cancer? Will cancer ever drop its rank as a notorious, complicated disease to an easily-managed one like catching a cold in medical textbooks? Well, with the 2018 Nobel Prize in medicine awarded to scientists whose pioneering work established the field of cancer immunotherapy, imagining a day when cancer management is as simple as cold treatment no longer seems implausible.
The seed for the emerging field of cancer immunotherapy was planted more than 25 years ago. In 1992, Dr. Tasuko Honjo at Kyoto University discovered the immune checkpoint inhibitor PD-1 (programmed cell death-1). Two years later, Dr. James P. Allison, through his work conducted at the University of California at Berkeley and Memorial Sloan Kettering Cancer Center in NY, demonstrated that blocking the function of another checkpoint inhibitor, CTLA-4 (cytotoxic T lymphocyte-associated antigen-4) could release the T cell brake caused by tumor cells to unleash the immune system toward attacking the tumor.
Now, flash forward 16 years later when Yervoy (ipilimumab), the first checkpoint inhibitor drug, which targets CTLA-4 and developed by Bristol-Myers Squibb, was approved by the United States FDA. Next in line was Opdivo (nivolumab), the first PD-1 inhibitor, developed by Ono Pharmaceutical and approved by Japan's regulatory body and later by the United States FDA. The launch of this first generation of cancer immunotherapies showcased the successful translation of basic science research into clinical treatment where the magic inherent ability of our immune system was harnessed to eradicate cancer.
Kyoto University
Identified the role of PD-1 in
cancer
MD Anderson Cancer Center at the University of Texas
Discovered how CTLA-4 is involved in tumor survival
Cancer immunotherapy can be passive, active or a hybrid of the two. In passive cancer immunotherapy the existing immune response to tumor cells are enhanced whereas in active immunotherapy immune cells are directed to attack tumor cells through targeting their cancer antigens. The immunotherapy developed by Allison and Honjo is an active type, where its principle lies in releasing the inhibitory checkpoint brakes on the immune system initially brought on by cancer cells. These molecular brakes enable our immune system to distinguish between self and foreign (i.e. tumor) cells before initiating a response and preventing harm to normal body cells by mistake. However, many cancer cells hijack these brakes to avoid targeting by the immune cells and ensure their survival.
The two checkpoint brakes that have so far been utilized in cancer immunotherapy are PD-1 and CTLA-4. Binding of the transmembrane PD-1 protein (PDCD1 or CD279) on T cells to its ligand PD-L1 (CD274) on normal cells inhibits immune cell activity (Fig. 1). However, upregulation of PD-L1 on cancer cells inhibits T cells' activation that might otherwise lead to an attack on cancer cells. Moreover, presence of PD-L1 on cancer cells can also inhibit cellular apoptosis to protect tumor cells from cytotoxic molecules released by immune cells. Similarly, overexpression of CTLA-4 in cancer cells, turns off the inhibitory checkpoint signal from CTLA-4 bound to its receptor, CD80/86 (Fig. 2). Normally, CTLA-4 on regulatory T cells competes with CD28 for binding to CD80/86 receptor on antigen-presenting cells. Therefore, in cancer patients T cells will not receive the co-stimulatory signal from CD28 required for eliciting an immune response to fight cancer.
Based on this shared basic mechanism of action, therapeutic antibodies are designed to block either of these checkpoint inhibitors or their receptors (Fig. 1,2). The result is T cell stimulation to elicit an immune response against tumor cells. Approved anti-PD-L1 drugs to this day are Atezolizumab (Tecentriq), Avelumab (Bavencio) and Durvalumab (Imfinzi), which have been successful in treating different types of cancer, such as bladder cancer, Merkel cell skin cancer and non-small cell lung cancer. Nivolumab (Opdivo) and Pembrolizumab (Keytruda) are also developed to target PD-1 to treat cancers such as melanoma, non-small lung cancer, renal carcinoma and bladder cancer. The drug Yervoy (Ipilimumab), designed to target CTLA-4, is also used to treat melanoma, with potential efficacies in lung, prostate, and bladder cancer.
Reviewing the results of the first generation of cancer immunotherapies showed that since PD-1 and CTLA-4 use slightly different mechanisms of action, they can be used in combination to obtain better synergistic anti-tumor effects. Recent efforts in engineering antibodies based on the unique molecular signature of each cancer patient has further advanced cancer immunotherapy. Now, a variety of immune cells, such as natural killer cells, dendritic cells, cytotoxic T cells and lymphokine-activated killer cells are used to generate cancer therapeutic antibodies to treat a variety of tumors. Moreover, immunotherapies targeting a variety of factors affecting tumor microenvironment, such as angiogenesis, metabolism and stroma, are under investigation to not only improve the effectiveness of existing tumor suppressors, but also to provide a novel alternative approach for personalized combination oncotherapy.
Immunotherapy has revolutionized cancer treatment options and opened a hopeful horizon for cancer patients. Patients now have expanded treatment options, allowing them to utilize their own bodies' defense system to fight cancer instead of relying solely on the conventional treatments of radiation and chemotherapy. Being designated as the American Society of Clinical Oncology (ASCO) Clinical Advance of the Year for the past 3 years and with this year's award going to adoptive cell immunotherapy, interest across diverse fields has peaked to develop more creative and novel approaches for stimulating the immune system to fight cancer.
Following the success of checkpoint inhibitors as first-line therapy in melanoma, the FDA approved the use of these inhibitors in other cancer types, including stomach, gastroesophageal, small cell lung and liver cancer and non-Hodgkin lymphoma, as well as first-line therapy in non-small cell lung cancer, renal cell carcinoma, and bladder cancer. In 2017, the FDA approved checkpoint inhibitors for treating metastatic solid tumors with unstable genomes, marking the first time the FDA approved any treatment based on a biomarker rather than an organ-specific tumor type. More importantly, the use of checkpoint inhibitors in cancer therapy has sparked numerous clinical trials investigating the efficacy of a combinatorial approach with dual-immunotherapies or combining immunotherapy with conventional cancer treatments in order to achieve greater targeting of tumor cells and improve treatment response in patients.
Development of immunotherapeutic options is also a giant step towards a personalized approach to cancer therapy. We now know that not every tumor is the same, even within one cancer type, nor does each tumor respond to treatment regimens in the same way. Conventional cancer therapies are not selective and will destroy not only tumor cells but also a patient's healthy cells. By invoking the immune system, immunotherapy forces immune cells to selectively target neoantigens on the surface of tumor cells, resulting in a robust anti-tumor response without damaging the patient's own cells. Selectively targeting a patient's unique cancer reduces the overall toxicity, improves the overall response and survival rates, and in the long run, makes treatment less expensive for the patient.
Despite the success of immunotherapy in the treatment of several types of cancer, significant challenges need to be overcome in order to make immunotherapy effective. Not all patients respond to the current FDA-approved checkpoint inhibitors and many tumor types are found to be resistant to these therapies. Indeed, among all metastatic melanoma patients around 22 percent respond to Yervoy and 60 percent to Opdivo. Tumor heterogeneity and the development of resistant tumor cells impedes clinical efficacy. Characterization of differing cancer types has revealed tumors have distinct morphological and phenotypic profiles. Additionally, genetic alterations, such as secondary genomic mutations or epigenetic changes, acquired by tumor cells leads to resistance to single-target cancer immunotherapy and thus treatment failure, highlighting the need for the development of low-toxicity combination immunotherapy and a better understanding of the mechanisms involved in the relapse of resistant tumors.
In addition, the long-term effects of immunotherapies can be serious and life-threatening. These effects include the development of acute-onset diabetes and organ damaging immune-mediated reactions involving the digestive system, liver, skin, nervous system, and heart. Likewise, invoking the immune system through cell therapy or therapeutic antibodies causes treatment-related toxicity resulting in cytokine release and capillary leak syndromes. Identification of new targets and assessing the efficacy of combinatorial strategies can improve the clinical success of cancer immunotherapies and reduce the autoimmune effects. The high cost of immune-based therapies also place a significant strain on not only patient expenses, but also on our health care system. To circumvent this, identification of predictive biomarkers to determine treatment response as well as early cancer or premalignant lesion biomarkers can aid in the development of more affordable treatment regimens and immunoprevention strategies.
Another exciting aspect of future cancer immunotherapy research is application of cell-based therapies to develop personalized cancer treatments. With the advent of genetic manipulation of a patient's T cells to fight cancer, adoptive cell therapies, such as chimeric antigen receptor (CAR) T cell therapy, are showing great promise. So far the FDA has approved the use of CAR-T cell immunotherapy for relapsed or refractory pediatric B cell precursor acute lymphoblastic leukemia (B-ALL) and adult B cell lymphoma, marking the first time that gene therapy is being approved in the United States. With CAR-T cell immunotherapy rapidly changing the landscape of cancer treatment, future research is focused on broadening the use of this therapy in not only hematological cancers but also in solid tumors.
With the fundamentals of the field already established and new multi-system approaches being developed, the future seems very bright and promising for immune-based cancer therapy. It is now hoped that future achievements would also include widespread accessibility and affordability among cancer patients, regardless of their income level or geographical location.
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