Limits...
New drugs, new toxicities: severe side effects of modern targeted and immunotherapy of cancer and their management

View Article: PubMed Central - PubMed

ABSTRACT

Pharmacological and cellular treatment of cancer is changing dramatically with benefits for patient outcome and comfort, but also with new toxicity profiles. The majority of adverse events can be classified as mild or moderate, but severe and life-threatening complications requiring ICU admission also occur. This review will focus on pathophysiology, symptoms, and management of these events based on the available literature.

While standard antineoplastic therapy is associated with immunosuppression and infections, some of the recent approaches induce overwhelming inflammation and autoimmunity. Cytokine-release syndrome (CRS) describes a complex of symptoms including fever, hypotension, and skin reactions as well as lab abnormalities. CRS may occur after the infusion of monoclonal or bispecific antibodies (MABs, BABs) targeting immune effectors and tumor cells and is a major concern in recipients of chimeric antigen receptor (CAR) modified T lymphocytes as well. BAB and CAR T-cell treatment may also be compromised by central nervous system (CNS) toxicities such as encephalopathy, cerebellar alteration, disturbed consciousness, or seizures. While CRS is known to be induced by exceedingly high levels of inflammatory cytokines, the pathophysiology of CNS events is still unclear. Treatment with antibodies against inhibiting immune checkpoints can lead to immune-related adverse events (IRAEs); colitis, diarrhea, and endocrine disorders are often the cause for ICU admissions.

Respiratory distress is the main reason for ICU treatment in cancer patients and is attributable to infectious agents in most cases. In addition, some of the new drugs are reported to cause non-infectious lung complications. While drug-induced interstitial pneumonitis was observed in a substantial number of patients treated with phosphoinositol-3-kinase inhibitors, IRAEs may also affect the lungs.

Inhibitors of angiogenetic pathways have increased the antineoplastic portfolio. However, vessel formation is also essential for regeneration and tissue repair. Therefore, severe vascular side effects, including thromboembolic events, gastrointestinal bleeding or perforation, hypertension, and congestive heart failure, compromise antitumor efficacy.

The limited knowledge of the pathophysiology and management of life-threatening complications relating to new cancer drugs presents a need to provide ICU staff, oncologists, and organ specialists with evidence-based algorithms.

No MeSH data available.


Immune checkpoints: physiological function and mode of action of inhibiting monoclonal antibodies (checkpoint inhibitors). CTLA-4 cytotoxic T-lymphocyte-associated protein 4, PD-1 programmed death receptor 1, PD-L1 ligand of PD-1, CPI checkpoint inhibitor(s), APC antigen-presenting cell, MHC major histocompatibility complex, TCR T-cell receptor
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC5391608&req=5

Fig1: Immune checkpoints: physiological function and mode of action of inhibiting monoclonal antibodies (checkpoint inhibitors). CTLA-4 cytotoxic T-lymphocyte-associated protein 4, PD-1 programmed death receptor 1, PD-L1 ligand of PD-1, CPI checkpoint inhibitor(s), APC antigen-presenting cell, MHC major histocompatibility complex, TCR T-cell receptor

Mentions: For decades, intensive research was focused on improving the immune system’s innate ability to fight against cancer cells. Ipilimumab [15] was the first player in a new class of so-called “checkpoint inhibitors”, which stimulate cellular immune effectors by blocking inhibitory signals. The physiological role of immune checkpoints such as CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), PD-1 or PD-2 (programmed death receptor-1 and -2), and their ligands is to limit immune reactions in order to avoid tissue damage and to allow tolerance. In various tumors these mechanisms are also used by cancer cells to overcome host defense barriers. Clinical trials with these new drugs in Hodgkin’s lymphoma and solid cancers like melanoma, non-small cell lung cancer, renal cell cancer, and colorectal cancer have shown impressive effects on patient outcome. Figure 1 illustrates biological functions of immune checkpoints and therapeutic interactions with their new inhibitors.Fig. 1


New drugs, new toxicities: severe side effects of modern targeted and immunotherapy of cancer and their management
Immune checkpoints: physiological function and mode of action of inhibiting monoclonal antibodies (checkpoint inhibitors). CTLA-4 cytotoxic T-lymphocyte-associated protein 4, PD-1 programmed death receptor 1, PD-L1 ligand of PD-1, CPI checkpoint inhibitor(s), APC antigen-presenting cell, MHC major histocompatibility complex, TCR T-cell receptor
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC5391608&req=5

Fig1: Immune checkpoints: physiological function and mode of action of inhibiting monoclonal antibodies (checkpoint inhibitors). CTLA-4 cytotoxic T-lymphocyte-associated protein 4, PD-1 programmed death receptor 1, PD-L1 ligand of PD-1, CPI checkpoint inhibitor(s), APC antigen-presenting cell, MHC major histocompatibility complex, TCR T-cell receptor
Mentions: For decades, intensive research was focused on improving the immune system’s innate ability to fight against cancer cells. Ipilimumab [15] was the first player in a new class of so-called “checkpoint inhibitors”, which stimulate cellular immune effectors by blocking inhibitory signals. The physiological role of immune checkpoints such as CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), PD-1 or PD-2 (programmed death receptor-1 and -2), and their ligands is to limit immune reactions in order to avoid tissue damage and to allow tolerance. In various tumors these mechanisms are also used by cancer cells to overcome host defense barriers. Clinical trials with these new drugs in Hodgkin’s lymphoma and solid cancers like melanoma, non-small cell lung cancer, renal cell cancer, and colorectal cancer have shown impressive effects on patient outcome. Figure 1 illustrates biological functions of immune checkpoints and therapeutic interactions with their new inhibitors.Fig. 1

View Article: PubMed Central - PubMed

ABSTRACT

Pharmacological and cellular treatment of cancer is changing dramatically with benefits for patient outcome and comfort, but also with new toxicity profiles. The majority of adverse events can be classified as mild or moderate, but severe and life-threatening complications requiring ICU admission also occur. This review will focus on pathophysiology, symptoms, and management of these events based on the available literature.

While standard antineoplastic therapy is associated with immunosuppression and infections, some of the recent approaches induce overwhelming inflammation and autoimmunity. Cytokine-release syndrome (CRS) describes a complex of symptoms including fever, hypotension, and skin reactions as well as lab abnormalities. CRS may occur after the infusion of monoclonal or bispecific antibodies (MABs, BABs) targeting immune effectors and tumor cells and is a major concern in recipients of chimeric antigen receptor (CAR) modified T lymphocytes as well. BAB and CAR T-cell treatment may also be compromised by central nervous system (CNS) toxicities such as encephalopathy, cerebellar alteration, disturbed consciousness, or seizures. While CRS is known to be induced by exceedingly high levels of inflammatory cytokines, the pathophysiology of CNS events is still unclear. Treatment with antibodies against inhibiting immune checkpoints can lead to immune-related adverse events (IRAEs); colitis, diarrhea, and endocrine disorders are often the cause for ICU admissions.

Respiratory distress is the main reason for ICU treatment in cancer patients and is attributable to infectious agents in most cases. In addition, some of the new drugs are reported to cause non-infectious lung complications. While drug-induced interstitial pneumonitis was observed in a substantial number of patients treated with phosphoinositol-3-kinase inhibitors, IRAEs may also affect the lungs.

Inhibitors of angiogenetic pathways have increased the antineoplastic portfolio. However, vessel formation is also essential for regeneration and tissue repair. Therefore, severe vascular side effects, including thromboembolic events, gastrointestinal bleeding or perforation, hypertension, and congestive heart failure, compromise antitumor efficacy.

The limited knowledge of the pathophysiology and management of life-threatening complications relating to new cancer drugs presents a need to provide ICU staff, oncologists, and organ specialists with evidence-based algorithms.

No MeSH data available.