Emerging role of immunotherapy of lung cancer

For decades, scientists and doctors thought immuno-therapy – treatments that harness the immune system to fight a disease – was of marginal benefit especially in lung cancer.  Recently, immunotherapy has had limited success in treatment of solid tumours except in the treatment of melanoma and renal cancers. 
Lung cancer was once thought of as a type of cancer that could evade the immune system by cytokine alterations, cellular immune dysfunction and antigen presentation defects. 
Today, lung cancer has emerged as an exciting new target of immune-based therapies and there are several approaches to immunotherapy that have shown promise in early clinical trials and have advanced to late-phase clinical trials and new development.

Dr Tan Yew Oo Medical Oncologist Farrer Park Medical Centre Singapore

Treatments for non-small cell lung cancer (NSCLC) have advanced the farthest, a number of new immune-based treatments for small cell lung cancer (SCLC), as well as for mesothelioma (another type of lung cancer), are also in clinical development.

These treatments can be broken into four main categories:
monoclonal antibodies, checkpoint inhibitors, therapeutic vaccines, and adoptive T cell transfer.  Monoclonal antibodies (mAbs) are molecules, generated in the laboratory, that target specific antigens on tumours.  Many mAbs are currently used in cancer treatment, and some appear to generate an immune response.  
Bevacizumab which targets vascular endothelial growth factor (VEGF), is FDA-approved for the treatment of non-squamous NSCLC. Several mAbs are currently being tested in clinical trials: Bavituximab, a mAb that targets an immune-suppressing molecule in tumours, is being tested with docetaxel versus docetaxel alone in phase III trial in patients with late stage non-squamous cell NSCLC (SUNRISE; NCT01999673), Patritumab, a human epidermal growth factor receptor-3 (HER3)-targeted mAb, given in combination with erlotinib is being tested in a phase III trial for patients with locally advanced or metastatic NSCLC (NCT02134015), Rilotumumab, a mAb targeting hepatocyte growth factor (HGF), is being tested in a phaseII/III trial as second line therapy for squamous cell NSCLC (NCT02154490) and Cixutumumab, a mAb targeting the insulin-like growth factor-1 receptor (IGF-1R) is being tested in a phase II trial for patients with NSCLC (NCT01263782)
Immune checkpoint inhibitors work by targeting molecules that serve as checks and balances in the regulation of immune responses. By blocking inhibitory molecules or, alternatively, activating stimulatory molecules, these treatments are designed to unleash or enhance pre-existing anti-cancer immune responses. 
There are several immune checkpoint proteins which diminish the antigen-specific immune response by limiting their magnitude and duration and include CTLA-4, PD-1, B7-H3, B7x, T-cell immunoglobulin and mucin-domain-containing molecule-3 (Tim-3) and B- and T-cell lymphocyte attenuator (BTLA). The monoclonal antibody to CTLA-4, ipilimumab blocks the interaction between CTLA-4 and its ligands CD80 and CD86, thereby promoting T-cell activation. 
It has been approved in melanoma but trials in NSCLC are in progress. PD-1 is named for its involvement in programmed cell death and PD-1 receptor binds its known ligands PD-L1, also known as B7-H1 and PD-L2 also known as B7-DC. 
Binding of PD-1 to its ligands causes T-cell inhibition and down regulation of T-cell response. Both PD-L1 and PD-L2 have been observed on cancer cells. Monoclonal antibodies that block both PD-1 (nivolumab and pembrolizumab) and PD-L1 (BMS936559, Medi4736 and MPDL3280A) aboragate the immune tolerance exerted by tumours through PD1/PD-L1 pathway.  
US FDA drug regulatory agency has recently granted pembrolizumab “breakthrough therapy” status for NSCLC.  Hopefully by targeting multiple inhibitory receptors in future clinical trials we may be able to improve the efficacy of anti-PD-1/PD-L1 antibody blockade in NSCLC. 
 Antigen specific immunotherapy or therapeutic vaccines target shared or tumour-specific antigens, including MAGE-3, which is expressed in 42% of lung cancers but absent in normal adult tissue, NY-ESO-1, which is expressed in 30% of lung cancers, p53, which is mutated in approximately 50% of lung cancers, survivin, and MUC1.
Another major avenue of immunotherapy for lung cancer is adoptive T cell transfer. In this approach, T cells are removed from a patient, genetically modified or treated with chemicals to enhance their activity, and then re-introduced into the patient with the goal of improving the immune system’s anti-cancer response. 
Several clinical trials of adoptive T cell transfer techniques are currently under way.  We are at the dawn of a major therapeutic avenue for treating cancer and lung cancer may show the way to treat advanced cancer using one of these modalities. Moving forward, we need confirmatory studies to validate the role of immune therapy in the treatment of both NSCLC and SCLC. 
We also need to delineate where immunotherapy fits in the landscape of cytotoxic therapies for lung cancer; should these therapies be given in a concurrent or sequential manner or the role of immunotherapy be based on molecular subtype of lung cancer. We need to elucidate the biomarkers of response while limiting toxicity to those those who will respond. This will be the key to the next frontier of treating lung cancer.
Source: 65Doctors Newsletters

 

 

Emerging role of immunotherapy of lung cancer

For decades, scientists and doctors thought immuno-therapy treatments that harness the immune system to fight a disease was of marginal benefit especially in lung cancer. Recently, immunotherapy has had limited success in treatment of solid tumours except in the treatment of melanoma and renal cancers. Lung cancer was once thought of as a type of cancer that could evade the immune system by cytokine alterations, cellular immune dysfunction and antigen presentation defects. Today, lung cancer has emerged as an exciting new target of immune-based therapies and there are several approaches to immunotherapy that have shown promise in early clinical trials and have advanced to late-phase clinical trials and new development. Dr Tan Yew Oo Medical Oncologist Farrer Park Medical Centre Singapore Treatments for non-small cell lung cancer (NSCLC) have advanced the farthest, a number of new immune-based treatments for small cell lung cancer (SCLC), as well as for mesothelioma (another type of lung cancer), are also in clinical development. These treatments can be broken into four main categories: monoclonal antibodies, checkpoint inhibitors, therapeutic vaccines, and adoptive T cell transfer. Monoclonal antibodies (mAbs) are molecules, generated in the laboratory, that target specific antigens on tumours. Many mAbs are currently used in cancer treatment, and some appear to generate an immune response. Bevacizumab which targets vascular endothelial growth factor (VEGF), is FDA-approved for the treatment of non-squamous NSCLC. Several mAbs are currently being tested in clinical trials: Bavituximab, a mAb that targets an immune-suppressing molecule in tumours, is being tested with docetaxel versus docetaxel alone in phase III trial in patients with late stage non-squamous cell NSCLC (SUNRISE; NCT01999673), Patritumab, a human epidermal growth factor receptor-3 (HER3)-targeted mAb, given in combination with erlotinib is being tested in a phase III trial for patients with locally advanced or metastatic NSCLC (NCT02134015), Rilotumumab, a mAb targeting hepatocyte growth factor (HGF), is being tested in a phaseII/III trial as second line therapy for squamous cell NSCLC (NCT02154490) and Cixutumumab, a mAb targeting the insulin-like growth factor-1 receptor (IGF-1R) is being tested in a phase II trial for patients with NSCLC (NCT01263782) Immune checkpoint inhibitors work by targeting molecules that serve as checks and balances in the regulation of immune responses. By blocking inhibitory molecules or, alternatively, activating stimulatory molecules, these treatments are designed to unleash or enhance pre-existing anti-cancer immune responses. There are several immune checkpoint proteins which diminish the antigen-specific immune response by limiting their magnitude and duration and include CTLA-4, PD-1, B7-H3, B7x, T-cell immunoglobulin and mucin-domain-containing molecule-3 (Tim-3) and B- and T-cell lymphocyte attenuator (BTLA). The monoclonal antibody to CTLA-4, ipilimumab blocks the interaction between CTLA-4 and its ligands CD80 and CD86, thereby promoting T-cell activation. It has been approved in melanoma but trials in NSCLC are in progress. PD-1 is named for its involvement in programmed cell death and PD-1 receptor binds its known ligands PD-L1, also known as B7-H1 and PD-L2 also known as B7-DC. Binding of PD-1 to its ligands causes T-cell inhibition and down regulation of T-cell response. Both PD-L1 and PD-L2 have been observed on cancer cells. Monoclonal antibodies that block both PD-1 (nivolumab and pembrolizumab) and PD-L1 (BMS936559, Medi4736 and MPDL3280A) aboragate the immune tolerance exerted by tumours through PD1/PD-L1 pathway. US FDA drug regulatory agency has recently granted pembrolizumab breakthrough therapy status for NSCLC. Hopefully by targeting multiple inhibitory receptors in future clinical trials we may be able to improve the efficacy of anti-PD-1/PD-L1 antibody blockade in NSCLC. Antigen specific immunotherapy or therapeutic vaccines target shared or tumour-specific antigens, including MAGE-3, which is expressed in 42% of lung cancers but absent in normal adult tissue, NY-ESO-1, which is expressed in 30% of lung cancers, p53, which is mutated in approximately 50% of lung cancers, survivin, and MUC1. Another major avenue of immunotherapy for lung cancer is adoptive T cell transfer. In this approach, T cells are removed from a patient, genetically modified or treated with chemicals to enhance their activity, and then re-introduced into the patient with the goal of improving the immune systems anti-cancer response. Several clinical trials of adoptive T cell transfer techniques are currently under way. We are at the dawn of a major therapeutic avenue for treating cancer and lung cancer may show the way to treat advanced cancer using one of these modalities. Moving forward, we need confirmatory studies to validate the role of immune therapy in the treatment of both NSCLC and SCLC. We also need to delineate where immunotherapy fits in the landscape of cytotoxic therapies for lung cancer; should these therapies be given in a concurrent or sequential manner or the role of immunotherapy be based on molecular subtype of lung cancer. We need to elucidate the biomarkers of response while limiting toxicity to those those who will respond. This will be the key to the next frontier of treating lung cancer. Source: 65Doctors Newsletters