Investigation on global cancer care Immunotherapy, a Rising Star in Cancer Treatment: Part I
Abstract: What is the role of our immune system? Fight against virus and bacteria! That’s right. Do you know that our immune system also protects us against internal insults such as cancer? With the rapid development of cancer immunotherapy, we are well on our way to leverage our own immune system to fight against cancer. In Part I of this article, we will be highlighting recent advances in one of the most promising cancer immunotherapies today – immune checkpoint blockade therapy.
Overview of cancer immunotherapy
The basis of the immune system
Our immune system is known for fighting off disease and foreign pathogens such as bacteria and viruses. This is accomplished through the recognition of foreign antigens. For example, during an infection, infected cells will express surface molecules or features that are different from what are normally “seen” by the immune system. Upon recognition of foreign antigens, specific B cells and T cells get activated, with B cells secreting antibodies to target the antigen while T cells either kill the infected cells or help modulate the immune response. Tumor cells are usually genetically unstable and harbor many mutations, leading to the expression of numerous tumor-specific antigens. In theory, these tumor cells are also “visible” to the immune system and could be targeted and killed by T cells.
Cancer cells can evade the immune surveillance system
The immune system is very powerful in that it can detect and kill pathogens, but it may mis-target and kill normal cells. To avoid autoimmune diseases and to contribute to the maintenance of immune tolerance, our body evolved an “immune checkpoint control” mechanism. However, tumors are capable of exploiting the checkpoint mechanisms to their advantage. They can overwhelm the immune system via multiple strategies, including alterations in antigen expression, interference with T-cell priming, and a spectrum of effects referred to as “immune editing”, whereby tumors manipulate their adjacent immune cells and the microenvironment during development to escape immune detection and eradication. Avoiding immune destruction is now considered as a novel hallmark of cancer.
What is cancer immunotherapy?
Cancer immunotherapy is treatment used to promote the patient’s own immune system or to administrate exogenously produced lymphocytes or antibodies to mount immune responses in order to eliminate malignant cells.
The immune system is our anti-cancer weapon that was acquired through evolution. By understanding the weaknesses of our immune system and the survival mechanisms of tumors, we can develop therapeutic interventions to help and support our immune system to fight against cancer. That’s why cancer immunotherapy is a fascinating field. In the following, we will discuss some specific cancer immunotherapies that have reached promising pre-clinical and clinical achievements in recent years.
Immune checkpoint blockade therapy
Checkpoint proteins CTLA-4, PD-1, and PD-L1 are the major players in the negative control of T cell priming and activation. Thus they may serve as excellent targets of cancer immunotherapy.
CTLA-4 blockade therapy opened a new era for immunotherapy
CTLA-4 was first discovered by Dr. Pierre Goldstein in 1987. Shortly after, CTLA-4 was found to be a key inhibitory receptor for T cells and was shown that inhibiting CTLA-4 could eliminate tumors in mice. These pre-clinical results inspired the development of multiple CTLA-4 blockade antibodies, including ipilimumab, which was developed by Bristol-Myers Squibb Company, for subsequent clinical studies. Ipilimumab was shown to be able to increase the overall survival of metastatic melanoma patients by 4 months in a phase III clinical trial, leading to its approval by the US Food and Drug Administration (FDA) in 2011 as an anti-melanoma drug. This was marked as the start of a new era for cancer immunotherapy. Recently, a meta-analysis study pooled data from several clinical trials and showed that around 20% of melanoma patients treated with ipilimumab were alive at the ten-year follow-up. This is very striking compared to existing therapies.
Although CTLA-4 blockade antibodies showed promising clinical responses in treating melanoma and some other cancers such as renal cell carcinoma, they also tend to induce immune-related adverse events, such as skin rash and inflammatory colitis. In addition, the relatively high toxicity of CTLA-4 blockade antibodies limits their usage in combination with other drugs, owing to the further increased toxicity.
PD-1/PD-L1 blockade therapy showed safer and more effective clinical responses
The next generation of immune checkpoint therapy blocks PD-1 (expressed on T cells) and its ligand PD-L1 (expressed on tumor cells and antigen presenting cells). PD-1 was first cloned by Tasuku Honjo in 1992. Several years later, PD-L1 was independently discovered by Lieping Chen and Gordon Freeman. Dr. Chen then found that PD-L1 was upregulated in multiple human cancers and tumor growth in mice was suppressed after blocking PD-L1 with PD-L1 antibody. Due to their great clinical potentials, several monoclonal antibodies (mAbs) that target either PD-1 or PD-L1 are actively tested in hundreds of large cohort clinical trials, including the PD-1 and PD-L1 mAbs developed by Xiaodong Wang and his BeiGene Company in China. Recently, FDA approved two PD-1 blocking mAbs, with nivolumab (Bristol-Myers Squibb) for melanoma, and squamous NSCLC and renal cell carcinoma, and pembrolizumab (Merck) for melanoma.
Nivolumab has been shown to induce 30%-40% objective response rate (ORR) in multiple melanoma clinical trials. It could extend the overall survival of squamous NSCLC patients compared with standard chemotherapy. In addition, nivolumab produced an 87% ORR in a recent phase I trial for refractory Hodgekin’s lymphoma. Pembrolizumab has also shown promising efficacy and safety to treat melanoma, advanced NSCLC, advanced gastric cancer, advanced bladder cancer and head and neck cancer, with ~20% ORR for most of the clinical trials. In addition, compared to anti-CTLA-4 mAb ipilimumab, two phase III trials showed that both nivolumab and pembrolizumab provided better clinical benefits in melanoma patients. Unlike CTLA-4 blockade therapy, PD-1/PD-L1 targeted mAbs showed much lower autoimmune toxicity. Therefore, anti-PD-1/PD-L1 therapy outcompetes anti-CTLA-4 therapy in all major clinical categories. Although, we still need to see if the persistent benefits of ilipimumab, which could last up to 10 years in some patients, will be seen in PD-1/PD-L1 blocking mAbs.
The combination therapy and beyond
Because a large number of cancer patients do not respond to single immune checkpoint blockade, combining different therapies are essential to achieve optimal clinical responses. . In a phase II trial, combining nivolumab and ipilimumab demonstrated much better response than ipilimumab alone (61% vs. 11%) in metastatic melanoma patients. Owing to their low toxicity, we could use anti-PD-1/PD-L1 mAbs as backbones to combine with other treatments.. In a phase II trial, combining nivolumab and ipilimumab demonstrated much better response than ipilimumab alone (61% vs. 11%) in metastatic melanoma patients. Combinations with other drugs, such as BRAF and MEK inhibitors, are currently also under pre-clinical and clinical investigations.
In addition to CTLA-4 and PD-1/PD-L1 pathways, the immune response is controlled and mediated by several other factors/components, including TIM3, IDO, TNF/TNFR superfamilies, B7-related proteins, soluble mediators and immune suppressive myeloid cells. Hundreds of ongoing studies are examining these immune components in the hope of validating novel targets for immunotherapy.
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