Toxicity of Checkpoint Inhibitors
Toxicity of Checkpoint Inhibitors
Immunologic checkpoint inhibitor is a new class of antineoplastic drugs which mechanism of action depends on the interaction with the immune system. The first in class was ipilimumab, anti-CTLA4, and soon the anti-PD1 (Programmed Death 1) and anti-PDL1 are expected to be available. Although the profile of adverse events is unique, they are predictable and, by complying with the guidelines available, the management of these drugs is safe in the great majority of patients. Here, it is provided a review of adverse events and their management.
For several years, metastatic melanoma treatment was based on dacarbazine. Results have been disappointing. Despite this, it has been the main choice for control arms, even in recent randomized controlled trials. Alternatively, immunotherapy has been studied for many years, as a promising therapy. The main reason for investment in research on immunotherapeutic agents is data supporting the idea that the immunologic system may interfere with melanoma outcome. Observations that support this theory are the findings of immune activity at spontaneous regression sites, melanoma with better outcome in patients who develop autoimmune events (e.g., vitiligo) and worse outcome in patients with immunodeficiency.
Many immunological agents, such as vaccines and cytokines, have been used in melanoma treatment. To the present, there is no single therapy vaccine considered active for metastatic melanoma or in the adjuvant scenario. The only positive results observed were in a single trial with gp100, which provided better results when added to high-dose of interleukin-2 (IL-2), but not enough to change practice.
Among cytokines, the only two drugs available for melanoma treatment are IL-2, in metastatic disease, and interferon-alfa in the adjuvant scenario. Despite their recognized activity, both therapies have yet to be universally adopted, mainly due to their toxicity profiles.
High-dose IL-2 has been approved based on data showing a long-term survival rate for approximately 5% of patients treated. No prospective molecular biomarker has been found to enrich these results, although clinical presentation was correlated with response rate. Complex and severe toxicity demanded more in terms of logistics and learning-curve for the treating institutions, in order to improve safety for patients. A significant point to consider in the IL-2 therapy was the dose adjustment according to toxicity: the number of doses administered depended on the toxicity, with the recommendation being to reach patients' tolerance threshold. This strategy, without the proper training of the entire treatment team, leads to higher risk of morbidity and mortality. Although there are defined guidelines, most community oncology centers have not adopted high-dose IL-2 as an alternative.
In the pursuit of the long-term benefit provided by immunotherapy, new agents have been developed. The new class of agents, called immunological checkpoint inhibitors, includes monoclonal antibodies without direct immune activity against tumor cells. They act through receptor blockade at specific points in the immune response. The first drug in this class was ipilimumab, an IgG antibody directed at the CTLA4 receptor of the T-Lymphocyte. This molecule is expressed on the T-cell surface after its activation and competes for B7 (a molecule of the antigen-presenting cell surface) interaction, which leads to an inhibitory signal for the T-cell. Through CTLA4 blockade, ipilimumab promotes a release of this inhibition and in turn, enhances the immune response. Its clinical activity has been demonstrated in two randomized clinical trials. The first trial dealt with previously treated melanoma patients, using four cycles of ipilimumabe at a dosage of 3 mg/kg. In this trial, the relative risk reduction for death was 34% for the patients that received ipilimumab, in comparison to those in the control arm (gp100). In a second randomized trial, with untreated patients, ipilimumab combined with dacarbazine was compared with dacarbazine alone. In this trial, four cycles of 10 mg/kg of ipilimumab were administered, followed by maintenance infusions every 12 weeks until progression. Again, overall survival benefit was verified, with a 28% risk reduction of mortality.
Although registration for ipilimumab in many countries was based in a single randomized trial, its development was rather long, with thousands of patients treated. This led to the important observation of toxicity and allowed the developers to define a comprehensive core of guidelines for patient management, which made the drug safe for community-based usage. To follow, toxicity and its managing guidelines will be reviewed and discussed.
Recently, three new drugs had their initial data presented. Nivolumab and lambrolizumab are both PD1 (Programmed Death 1) blockers. MPDL3280A is a PD-L1 inhibitor. PD1, is a T-Lymphocyte surface receptor which promotes inhibition of cell immune response upon interaction with its ligands: PD-L1 and PD-L2. It promotes such reduction by a rapid up regulation at the antigen cell presentation, causing an acute inhibitory signal. Another mechanism of T-cell inactivation is through chronic exposure to antigens and, in particular, PD-L1. This may be observed in tumor infiltrating lymphocytes, which become exhausted. The blockade of PD1 interaction with its ligands, promotes improvement of acute T-cell activation, and also restores chronic activity, revert the exhaustion. The toxicity profile discussed in the text to follow will be based on the initial data presented on these drugs.
Abstract and Introduction
Abstract
Immunologic checkpoint inhibitor is a new class of antineoplastic drugs which mechanism of action depends on the interaction with the immune system. The first in class was ipilimumab, anti-CTLA4, and soon the anti-PD1 (Programmed Death 1) and anti-PDL1 are expected to be available. Although the profile of adverse events is unique, they are predictable and, by complying with the guidelines available, the management of these drugs is safe in the great majority of patients. Here, it is provided a review of adverse events and their management.
Introduction
For several years, metastatic melanoma treatment was based on dacarbazine. Results have been disappointing. Despite this, it has been the main choice for control arms, even in recent randomized controlled trials. Alternatively, immunotherapy has been studied for many years, as a promising therapy. The main reason for investment in research on immunotherapeutic agents is data supporting the idea that the immunologic system may interfere with melanoma outcome. Observations that support this theory are the findings of immune activity at spontaneous regression sites, melanoma with better outcome in patients who develop autoimmune events (e.g., vitiligo) and worse outcome in patients with immunodeficiency.
Many immunological agents, such as vaccines and cytokines, have been used in melanoma treatment. To the present, there is no single therapy vaccine considered active for metastatic melanoma or in the adjuvant scenario. The only positive results observed were in a single trial with gp100, which provided better results when added to high-dose of interleukin-2 (IL-2), but not enough to change practice.
Among cytokines, the only two drugs available for melanoma treatment are IL-2, in metastatic disease, and interferon-alfa in the adjuvant scenario. Despite their recognized activity, both therapies have yet to be universally adopted, mainly due to their toxicity profiles.
High-dose IL-2 has been approved based on data showing a long-term survival rate for approximately 5% of patients treated. No prospective molecular biomarker has been found to enrich these results, although clinical presentation was correlated with response rate. Complex and severe toxicity demanded more in terms of logistics and learning-curve for the treating institutions, in order to improve safety for patients. A significant point to consider in the IL-2 therapy was the dose adjustment according to toxicity: the number of doses administered depended on the toxicity, with the recommendation being to reach patients' tolerance threshold. This strategy, without the proper training of the entire treatment team, leads to higher risk of morbidity and mortality. Although there are defined guidelines, most community oncology centers have not adopted high-dose IL-2 as an alternative.
In the pursuit of the long-term benefit provided by immunotherapy, new agents have been developed. The new class of agents, called immunological checkpoint inhibitors, includes monoclonal antibodies without direct immune activity against tumor cells. They act through receptor blockade at specific points in the immune response. The first drug in this class was ipilimumab, an IgG antibody directed at the CTLA4 receptor of the T-Lymphocyte. This molecule is expressed on the T-cell surface after its activation and competes for B7 (a molecule of the antigen-presenting cell surface) interaction, which leads to an inhibitory signal for the T-cell. Through CTLA4 blockade, ipilimumab promotes a release of this inhibition and in turn, enhances the immune response. Its clinical activity has been demonstrated in two randomized clinical trials. The first trial dealt with previously treated melanoma patients, using four cycles of ipilimumabe at a dosage of 3 mg/kg. In this trial, the relative risk reduction for death was 34% for the patients that received ipilimumab, in comparison to those in the control arm (gp100). In a second randomized trial, with untreated patients, ipilimumab combined with dacarbazine was compared with dacarbazine alone. In this trial, four cycles of 10 mg/kg of ipilimumab were administered, followed by maintenance infusions every 12 weeks until progression. Again, overall survival benefit was verified, with a 28% risk reduction of mortality.
Although registration for ipilimumab in many countries was based in a single randomized trial, its development was rather long, with thousands of patients treated. This led to the important observation of toxicity and allowed the developers to define a comprehensive core of guidelines for patient management, which made the drug safe for community-based usage. To follow, toxicity and its managing guidelines will be reviewed and discussed.
Recently, three new drugs had their initial data presented. Nivolumab and lambrolizumab are both PD1 (Programmed Death 1) blockers. MPDL3280A is a PD-L1 inhibitor. PD1, is a T-Lymphocyte surface receptor which promotes inhibition of cell immune response upon interaction with its ligands: PD-L1 and PD-L2. It promotes such reduction by a rapid up regulation at the antigen cell presentation, causing an acute inhibitory signal. Another mechanism of T-cell inactivation is through chronic exposure to antigens and, in particular, PD-L1. This may be observed in tumor infiltrating lymphocytes, which become exhausted. The blockade of PD1 interaction with its ligands, promotes improvement of acute T-cell activation, and also restores chronic activity, revert the exhaustion. The toxicity profile discussed in the text to follow will be based on the initial data presented on these drugs.