Abstract:CI inhibitors have different toxicity profiles to chemotherapy. These findings are useful for patient counselling and planning of future trials.
“…The combination of pP1A with ICB further decreased tumor growth even if the doses of ICBs used in this study were lower than others that employed the same therapeutic combination (100 µg compared to 200–250 µg per dose, per antibody) 3 , 11 . This encouraging result suggests the possibility to reduce the dose of ICB when they are administered in combination with DNA vaccination, to decrease the toxicities associated to these antibodies in human patients 12 . Figure 1 Therapeutic combination of pP1A and ICBs (anti-CTLA4/PD1).…”
DNA vaccination against cancer has become a promising strategy for inducing a specific and long-lasting antitumor immunity. However, DNA vaccines fail to generate potent immune responses when used as a single therapy. To enhance their activity into the tumor, a DNA vaccine against murine P815 mastocytoma was combined with antibodies directed against the immune checkpoints CTLA4 and PD1. The combination of these two strategies delayed tumor growth and enhanced specific antitumor immune cell infiltration in comparison to the corresponding single therapies. The combination also promoted IFNg, IL12 and granzyme B production in the tumor microenvironment and decreased the formation of liver metastasis in a very early phase of tumor development, enabling 90% survival. These results underline the complementarity of DNA vaccination and immune checkpoint blockers in inducing a potent immune response, by exploiting the generation of antigen-specific T cells by the vaccine and the ability of immune checkpoint blockers to enhance T cell activity and infiltration in the tumor. These findings suggest how and why a rational combination therapy can overcome the limits of DNA vaccination but could also allow responses to immune checkpoint blockers in a larger proportion of subjects.
“…The combination of pP1A with ICB further decreased tumor growth even if the doses of ICBs used in this study were lower than others that employed the same therapeutic combination (100 µg compared to 200–250 µg per dose, per antibody) 3 , 11 . This encouraging result suggests the possibility to reduce the dose of ICB when they are administered in combination with DNA vaccination, to decrease the toxicities associated to these antibodies in human patients 12 . Figure 1 Therapeutic combination of pP1A and ICBs (anti-CTLA4/PD1).…”
DNA vaccination against cancer has become a promising strategy for inducing a specific and long-lasting antitumor immunity. However, DNA vaccines fail to generate potent immune responses when used as a single therapy. To enhance their activity into the tumor, a DNA vaccine against murine P815 mastocytoma was combined with antibodies directed against the immune checkpoints CTLA4 and PD1. The combination of these two strategies delayed tumor growth and enhanced specific antitumor immune cell infiltration in comparison to the corresponding single therapies. The combination also promoted IFNg, IL12 and granzyme B production in the tumor microenvironment and decreased the formation of liver metastasis in a very early phase of tumor development, enabling 90% survival. These results underline the complementarity of DNA vaccination and immune checkpoint blockers in inducing a potent immune response, by exploiting the generation of antigen-specific T cells by the vaccine and the ability of immune checkpoint blockers to enhance T cell activity and infiltration in the tumor. These findings suggest how and why a rational combination therapy can overcome the limits of DNA vaccination but could also allow responses to immune checkpoint blockers in a larger proportion of subjects.
“…Immune‐related demyelinating polyradiculoneuropathy (irDP) is a rare psn‐irAEs, estimated to occur in 0.1% to 0.3% of patients treated with anti‐PD‐1 and/or anti‐CTLA‐4 agents . However, a meta‐analysis on 20 clinical trials including 10 794 patients with five different types of cancer showed the prevalence of peripheral neuropathy to be much higher (7.6% for anti‐PD‐1 and 3.0% for anti‐PD‐L1 agents) . Differences in case ascertainment (eg, clinical vs instrumental diagnosis) might explain the discrepancies across these epidemiological data.…”
Section: Clinical Syndromes and Presentationsmentioning
Immune checkpoint inhibitors (ICIs) are increasingly used and are becoming the standard of care in the treatment of various tumor types. Despite the favorable results in terms of oncological outcomes, these treatments have been associated with a variety of immune-related adverse events (irAEs). Neurological irAEs are rare but potentially severe. Neuromuscular disorders represent the most common neurological irAEs following anti-PD-1, anti-PD-L1, and anti-CTLA-4 treatment, and include myositis, myasthenia gravis, and demyelinating polyradiculoneuropathy. Instrumental findings may differ from typical neuromuscular disorders occurring outside ICIs treatment.Despite initial severity, neurological irAEs often respond to immune-modulating therapies. Prompt irAEs diagnosis, ICIs discontinuation, and early treatment with corticosteroids, together with patient education and a multi-disciplinary approach, are important for optimizing clinical outcomes. Intravenous immunoglobulin, plasma exchange, and other immune-modulating treatments should be considered in more severe cases. Consideration of re-challenging with the same immunotherapy drug may be given in some cases, based on clinical picture and initial severity of irAEs.
K E Y W O R D SCTLA-4, demyelinating polyradiculoneuropathy, immune checkpoint inhibitor, myasthenia gravis, myositis, nivolumab, PD-1, PD-L1, pembrolizumab, peripheral neuropathy
“…Several clinical trials using antibodies targeting the interaction of PD-1 and PD-L1 for cancer treatment have shown promising abilities in prolonging survival, but not all patients respond to PD-1/PD-L1 inhibitors (97). In addition, clinical results have also shown that anti-PD-1 or anti-PD-L1 treatment caused TRAEs and IRAEs, although anti-PD-1/PD-L1 drugs have shown lower toxicity than standard chemotherapy (98). Most seriously, AEs caused by these antibodies sometimes could lead to treatment discontinuation and treatment interruption (98).…”
Section: The Current Optimization Of Anti-pd-1/pd-l1 Treatment Strategymentioning
Targeting PD-L1 and PD-1 interactions is a relatively new therapeutic strategy used to treat cancer. Inhibitors of PD-1/PD-L1 include peptides, small molecule chemical compounds, and antibodies. Several approved antibodies targeting PD-1 or PD-L1 have been patented with good curative effect in various cancer types in clinical practices. While the current antibody therapy is facing development bottleneck, some companies have tried to develop PD-L1 companion tests to select patients with better diagnosis potential. Meanwhile, many companies have recently synthesized small molecule inhibitors of PD-1/PD-L1 interactions and focused on searching for novel biomarker to predict the efficacy of anti-PD-1/PD-L1 drugs. This review summarized clinical studies and patent applications related to PD-1/PD-L1 targeted therapy and also discussed progress in inhibitors of PD-1/PD-L1.
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