Discovery of Cancer Therapy by Inhibition of Negative Immune Regulation Essay
Discovery of Cancer Therapy by Inhibition of Negative Immune Regulation Essay
Cancer is a common term for a group of diseases caused by uncontrolled cell proliferation and migration. This results in abnormal growth of a tumor mass, first within an organ, then infiltrating adjacent tissues. Eventually, cancer cells can also colonize distant organs via blood or lymphatic vessels, so called metastases, causing morbidity and death. The symptoms, course and prognosis of the disease vary depending on the tissue origin. The risk of cancer increases with age and the remarkably longer life span of the world population contributes to cancer as an increasing problem. Life style and environmental factors add to this development, with smoking as the most important factor. Discovery of Cancer Therapy by Inhibition of Negative Immune Regulation Essay.
Pros and cons to essay on Immune Checkpoint Inhibitors: Advances and Impact in Neuro-Oncology
James P. Allison studied a known protein that functions as a brake on the immune system, CTLA-4. He developed an antibody to CTLA-4 to block the immune system brake. He reasoned that the T cells would be unleashed and become more active and hopefully attack the cancer cells. The key experiment was performed in 1994. The results were spectacular. The mice treated with the anti-CTLA-4 antibody were cured from cancer, while the control mice developed large tumours. This seminal study represents the birth of a new concept for immunotherapy. Today often referred to as immune checkpoint inhibition. Allison was eager to apply it for the benefit of patients. A small biotech company took on the challenge to produce the human antibody and a few years later the first clinical trial started with 40 patients suffering from metastatic melanoma, the pigmented cancer of the skin. Some of the patients showed striking responses – the tumours shrank, and could even disappear. Such results had never been seen before in this patient group. Despite side effects, the results were positive enough to start a long series of larger trials conducted by clinical colleagues.
In 1992, 4 years before Allison’s observations on Discovery of Cancer Therapy by Inhibition of Negative Immune Regulation Essay.CTLA-4 were published, Tasuko Honjo discovered PD-1 as a novel member of the immunoglobulin gene superfamily. His new observation published in The EMBO Journal suggested that the PD-1 protein may be involved in the classical type of programmed cell death.[Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. Ishida Y, Agata Y, Shibahara K, Honjo T EMBO J. 1992 Nov; 11(11):3887-95.] In 1999, Honjo et al. published another study in Immunity, This suggested that PD-1 serves as a negative regulator of immune responses. One year later in the Journal of Experimental Medicine, Honjo et al. described that the ligand of PD-1 (PD-L1) plays a central role in the inhibition of T-cell receptor-mediated lymphocyte proliferation and cytokine secretion. PD-1 and PD-L1 engagement may subsequently determine the extent of immune responses at sites of inflammation. In 2005, Honjo’s laboratory published another study in International
Definitely, the discovery and evolution of immune checkpoint inhibitors is one of the most exciting advances in cancer immunotherapy. Discovery of Cancer Therapy by Inhibition of Negative Immune Regulation Essay. Non-CNS tumors, specifically, have experienced impressive responses with long-lasting survival benefits. As CNS tumors can develop multiple mechanisms for immune-resistance, combinations using multiple checkpoint inhibitors targeting both CTLA-4 and PD-1, with or without other immune-based strategies may be the most effective means in generating an antitumor immune response. Awareness and multidisciplinary management of immune-related adverse events and developing cost-effective strategies for treatment are also necessary to ensure the optimal clinical benefit from these
References
Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation.
Friedman CF, Proverbs-Singh TA, Postow MA. Treatment of the immune-related adverse effects of immune checkpoint inhibitors: A review. JAMA Oncol. 2016;2:1346–53.
Hodi FS, Mihm MC, Soiffer RJ, Haluska FG, Butler M, Seiden MV, et al. Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients.
Ishida Y, Agata Y, Shibahara K, Honjo T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death.
Nishimura H, Nose M, Hiai H, Minato N, Honjo T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity.
For many decades, the standard treatments for cancer have been mostly surgery, chemotherapy and/or radiation therapy. Despite these treatments, most patients with advanced malignant disease had miserable survival rates. New thinking and novel strategies for cancer therapy were badly needed. Cancer immunotherapy seemed to be the answer. Discovery of Cancer Therapy by Inhibition of Negative Immune Regulation Essay . There is a long history of efforts to take advantage of a patient’s own immune system as a therapeutic modality for cancer. The earliest effort may trace back to the observation of William B. Coley, who as a surgeon correlated the occurrence of postoperative infection with improved clinical outcomes in cancer patients in 1893 [1]. Later on, several modalities of cancer immunotherapies were approved, including bacillus Calmette-Guerin, interferon-α, and interleukin-2 (IL-2). The work with IL-2 in treating cancer substantiated the important role of adaptive immunity in cancer therapy.
Through decades of hard work, we started to gain an understanding of the basic mechanisms of T cell activation. Naïve T cells acquire two key signals from antigen presenting cells (APC), with the first one being presentation of the antigen-derived epitope peptides in the context of MHC class antigens to the T-cell receptor on T cells. The second signal is mainly through the interaction of co-stimulatory molecules, such as CD28, expressed on most T cells with its natural ligands CD80 and CD86 on APC. These co-stimulatory signals, or so called T-cell “accelerators”, are required to trigger a full-blown immune response against cancer or infectious diseases. Nevertheless, although we had accumulated quite a bit of knowledge about antitumor immunity prior to 2010, clinical studies of cancer immunotherapies had been mostly disappointing. Various cancer vaccines had generated poor clinical responses in thousands of cancer patients, and so did adoptive transfer of tumor-infiltrating lymphocytes (TILs) [2]. During the mid-1990s, a lot of investigators had doubts about the future of cancer immunotherapy. Discovery of Cancer Therapy by Inhibition of Negative Immune Regulation Essay.
A new concept of regulated immunity and new principle for immunotherapy
One key intrinsic property of the immune system is to maintain a delicate homeostasis, in order to get rid of pathogens, yet not elicit autoimmune diseases. Therefore, in the 1990s, investigators hypothesized that “brakes” as well as “accelerators” exist for the activated T cells.
Allison studied the T-cell protein CTLA-4 in the 1990s. He and other teams of scientists had made the observation that CTLA-4 functions as a brake on T cell activities. He had developed an antibody that could block CTLA-4 function. He set out to investigate the hypothesis that CTLA-4 blockade could release the T-cell brake to allow the immune system to attack cancer cells. Mice with cancer had been cured by treatment with the anti-CTLA-4 antibody thanks to unlocked antitumor T-cell activity [3, 4]. He continued intense efforts to develop the strategy into a cancer therapy regimen for human. In 2010, a pivotal clinical study showed striking effects in patients with advanced melanoma.
Honjo discovered PD-1 expressed on the surface of T-cells in 1992 [5]. It took many years of work to unravel its role in immune response. The results showed that PD-1 operates by a different mechanism from CTLA-4. In preclinical studies, Honjo and others showed that PD-1 blockade was a promising strategy in the fight against cancer [6, 7]. In 2012, a key clinical study demonstrated obvious efficacy of anti-PD-1 antibody in cancer patients. This treatment led to long-term remission and a possible cure for multiple patients with metastatic cancer.
The work done by Allison, Honjo, together with many others, have opened up a new avenue for cancer immunotherapy, which led to approval by the authorities for the use of immune checkpoint blockade to treat at least ten types of cancers so far, and many more to come.
The Nobel Prize work opens up a bright future for cancer immunotherapy
The Prize winning work launched a new field that now goes far beyond CTLA-4 and PD-1. At least three areas of ongoing research may lead us to novel fundamental knowledge of immunology and brand new regimens of immunotherapy for cancer and other immunological diseases. First, other co-inhibitory signaling pathways, such as HVEM-BTLA and Galectin-9-TIM3, are being studied in cancer and other diseases [8]. Once we know more about these inhibitory signaling pathways, we may design rational combinational strategies to concurrently target two or more inhibitory pathways to gain better therapeutic efficacy. Secondly, one rational strategy would be to combine immune checkpoint blockade with other immunotherapy regimens or other standard of care regimens in order to eliminate primary cancer and metastases more effectively.Discovery of Cancer Therapy by Inhibition of Negative Immune Regulation Essay. One such strategy has been to combine anti-PD-1/PD-L1 or anti-CTL4 with oncolytic viruses (OVs). This combinatorial strategy deems to be rational as OVs induce inflammation in cancer, which in turn increase TILs, upregulate immune checkpoint molecules such as PD-1/PD-L1, and as a result, transforms a “cold” tumor to a “hot” one immunologically [9, 10]. As we have suggested in our recent study, this combinatorial therapy may be applicable to a much wider population of cancer patients than the monotherapies do. So far, data from the first two clinical trials demonstrated this combination of OV with immune checkpoint antibody achieved much higher efficacy with shown toxicity in patients with advanced melanoma [11, 12]. Finally, other types of cancer immunotherapies, including adoptive transfer of CAR T cells [13], TCR-modified T cells [14], and cancer vaccines using neo-antigens [15, 16], have made significant progress in recent years, and has shown promise in clinics. It is envisioned that some selective rational combinations of these anti-cancer agents with immune checkpoint blockade will work more effectively on some cancer patients as personalized medicine.
In summary, after this major recognition of the importance of immunity, investigators from this field are highly excited and will spare no efforts to make this regimen of cancer therapeutics more efficacious. The future of this therapy looks brighter. Discovery of Cancer Therapy by Inhibition of Negative Immune Regulation Essay.
