Significant enthusiasm currently exists for new immunotherapeutic strategies: blocking the interaction between programmed death-1 receptor on T-cells and programmed death-ligand 1 on tumor cells to boost immune system stimulation to fight cancer. Immunomodulation with the antiprogrammed death-1/programmed death-ligand 1 monoclonal antibodies has shown to mediate tumor shrinkage and extend overall survival from several pivotal phase I/II studies in melanoma, renal cell carcinoma, and non-small cell lung cancer. This has prompted multiple large ongoing phase III trials with the expectation for fast-track FDA approvals to satisfy unmet medical needs. Compounds targeting the programmed death-1 pathway that are in clinical trials fall into two major categories, namely antiprogrammed death-1 antibodies: Nivolumab, MK-3475, and pidilizumab; and antiprogrammed death-ligand 1 antibodies: MPDL3280A, BMS-936559, MEDI4736, and MSB0010718C. We reviewed the clinical efficacy and safety of each compound based upon major registered clinical trials and published clinical data. Overall, response rate of more than 20% is consistently seen across all these trials, with maximal response of approximately 50% achieved by certain single antiprogrammed death-1 agents or when used in combination with cytotoxic T-lymphocyte antigen-4 blockade. The responses seen are early, durable, and have continued after treatment discontinuation. Immune-related adverse events are the most common side effects seen in these clinical trials. Overall, the skin and gastrointestinal tract are the most common organ systems affected by these compounds while hepatic, endocrine, and neurologic events are less frequent. These side effects are low grade, manageable, and typically resolve within a relatively short time frame with a predictable resolution pattern given proper management. We therefore propose detailed guidelines for management of major immune-related adverse events that are anticipated with antiprogrammed death-1/programmed death-ligand 1 therapies based on general experience with other monoclonal antibodies and the established management algorithms for immune-related adverse events for cytotoxic T-lymphocyte antigen-4 blockade with ipilimumab. We anticipate that the antiprogrammed death-1 strategy will become a viable and crucial clinical strategy for cancer therapy.
MicroAbstract The goal of the present study was to evaluate a novel prospective influenza vaccination strategy in patients with plasma cell disorders. Fifty-one patients were treated with a two dose series of high-dose inactivated trivalent influenza vaccine. This vaccination strategy was well tolerated led to very high rates of seroprotection against influenza. Background Patients with multiple myeloma (MM) and other plasma cell disorders are highly susceptible to influenza infections, which are major causes of morbidity in this population despite routine administration of seasonal influenza vaccination. Existing data are limited by small and retrospective studies, which suggest poor seroprotection rates of less than 20% following standard influenza vaccination in MM. Methods Patients with plasma cell dyscrasia (N=51) were treated with a two dose series of high-dose inactivated trivalent influenza vaccine over the 2014–2015 influenza season. Laboratory-confirmed influenza infections were identified through seasonal surveillance, sera were collected for influenza hemagglutination inhibition (HAI) titer assays, and logistic regression models were used to identify clinical correlates of HAI serologic responses. Findings Influenza vaccine was well tolerated without any vaccine-related ≥grade two adverse events. Only three patients (6%) experienced laboratory-confirmed influenza. Rates of HAI seroprotection against all three vaccine strains (influenza B, H1N1, and H3N2) increased from 4% at baseline to 49% and 65% following one and two doses, respectively. Risk factors associated with lower likelihood of HAI serologic response included plasma cell disorder requiring therapy, disease response assessment < partial response, or active conventional chemotherapy. Alternatively, active therapy with an immunomodulatory drug alone or with proteasome inhibitor was associated with a higher likelihood of HAI serologic response. Conclusions These data demonstrate that in contrast to historically poor results with standard influenza vaccination, this novel high-dose booster vaccination strategy leads to high rates of seroprotection. Randomized controlled studies are needed to compare this to standard vaccination strategy.
Patients with plasma cell dyscrasias (PCDs) experience an increased burden of influenza, and current practice of single-dose annual influenza vaccination yields suboptimal protective immunity in these patients. Strategies to improve immunity to influenza in these patients are clearly needed. We performed a randomized, double-blind, placebo-controlled clinical trial comparing tandem Fluzone High-Dose influenza vaccination with standard-of-care influenza vaccination. Standard-of-care vaccination was single-dose age-based vaccination (standard dose, <65 years; high dose, ≥65 years), and patients in this arm received a saline placebo injection at 30 days. A total of 122 PCD patients were enrolled; 47 received single-dose standard-of-care vaccination, and 75 received 2 doses of Fluzone High-Dose vaccine. Rates of hemagglutinin inhibition (HAI) titer seroprotection against all 3 strains (H1N1, H3N2, and influenza B) were significantly higher for patients after tandem high-dose vaccination vs control (87.3% vs 63.2%; P = .003) and led to higher seroprotection at the end of flu season (60.0% vs 31.6%; P = .04). These data demonstrate that tandem high-dose influenza vaccination separated by 30 days leads to higher serologic HAI titer responses and more durable influenza-specific immunity in PCD patients. Similar vaccine strategies may also be essential to achieve protective immunity against other emerging pathogens such as novel coronavirus in these patients. This trial was registered at www.clinicaltrials.gov as #NCT02566265.
To our knowledge, this is the first report of two patients with documented IR with panitumumab being desensitized successfully with cetuximab. Though anecdotal reports suggest safety of panitumumab in patients following IR with cetuximab, panitumumab can also cause severe IR. Our experience suggests that in case of limited options, such patients can be successfully challenged with cetuximab in a hospital after appropriate desensitization and premedication. Further studies focusing on desensitization and identifying hypersensitivity profile of different anti-epidermal growth factor receptor antibodies are warranted.
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