Management and Prevention of Cellular-Therapy-Related Toxicity: Early and Late Complications.

Chimeric Antigen Receptor T (CAR-T) cell therapy has dramatically changed prognosis and treatment of relapsed and refractory hematologic malignancies. Currently the 6 FDA approved products target various surface antigens. While CAR-T therapy achieves good response, life-threatening toxicities have been reported. Mechanistically, can be divided into two categories: (1) toxicities related to T-cell activation and release of high levels of cytokines: or (2) toxicities resulting from interaction between CAR and CAR targeted antigen expressed on non-malignant cells (i.e., on-target, off-tumor effects). Variations in conditioning therapies, co-stimulatory domains, CAR T-cell dose and anti-cytokine administration, pose a challenge in distinguishing cytokine mediated related toxicities from on-target, off-tumor toxicities. Timing, frequency, severity, as well as optimal management of CAR T-cell-related toxicities vary significantly between products and are likely to change as newer therapies become available. Currently the FDA approved CARs are targeted towards the B-cell malignancies however the future holds promise of expanding the target to solid tumor malignancies. Further highlighting the importance of early recognition and intervention for early and late onset CAR-T related toxicity. This contemporary review aims to describe presentation, grading and management of commonly encountered toxicities, short- and long-term complications, discuss preventive strategies and resource utilization.

Cirrhotic coagulopathy: A rebalanced hemostasis.

Cirrhosis has been regarded as a hypocoagulable state associated with an increased risk of bleeding. But patients with cirrhosis also have a high incidence of thrombotic complications, challenging this dogma. We now recognize that in cirrhosis there is a simultaneous decrease in both clotting and anticlotting factors, leading to a new equilibrium. Conventional coagulation tests such as the platelet count and prothrombin time do not assess the reduced anticoagulation factors in cirrhosis and overestimate the bleeding risk, and any intervention based on these test results can lead to thrombotic complications. This article reviews the changes in hemostasis associated with cirrhosis, newer tests for assessing coagulation, and preprocedural minimization of coagulopathy.

Update to coagulopathy in COVID-19: Manifestations and management.

Severe COVID-19 illness is associated with intense inflammation, leading to high rates of thrombotic complications that increase morbidity and mortality. Markedly elevated levels of D-dimer with normal fibrinogen levels are the hallmark laboratory findings of severe COVID-19-associated coagulopathy. Prophylaxis against venous thromboembolism is paramount for all hospitalized patients with COVID-19, with more aggressive prophylaxis and screening recommended for critically ill patients with D-dimer levels above 3.0 µg/mL. Point-of-care ultrasonography is the imaging method of choice for patients at high risk, as it entails minimal risk of exposing providers to the virus.

Convalescent plasma for COVID-19: Promising, not proven.

While promising, convalescent plasma remains experimental and is not proven effective for COVID-19. In addition, many questions remain regarding the accuracy and predictive value of antibody testing of donors and patients, optimal donor selection, optimal timing, and selection of patients most likely to benefit. Until these questions are answered, convalescent plasma should ideally be used in the context of well-designed clinical trials.

Coagulopathy in COVID-19: Manifestations and management.

Severe COVID-19 illness is associated with intense inflammation, leading to high rates of thrombotic complications that increase morbidity and mortality. Markedly elevated levels of D-dimer with normal fibrinogen levels are the hallmark laboratory findings of severe COVID-19- associated coagulopathy. Prophylaxis against venous thromboembolism is paramount for all hospitalized patients, with more aggressive prophylaxis and screening recommended for patients with D-dimer levels above 3.0 µg/mL. Point-of-care ultrasonography is the imaging method of choice for patients at high risk, as it entails minimal risk of exposing providers to the virus.

P60-c-src suppresses apoptosis through inhibition of caspase 8 activation in hepatoma cells, but not in primary hepatocytes.

BACKGROUND/AIMS: Failure to induce apoptosis triggered by members of the death receptor family has been described in hepatocellular carcinoma (HCC) and sensitization of malignant cells to pro-apoptotic molecules such as TRAIL has been proposed as an alternative cancer therapy. Limiting to this approach are the resistance of many tumor cells to TRAIL and safety concerns about the toxicity of TRAIL in normal hepatocytes. METHODS: We here explored the possibility that the protooncogene c-Src, known to be overexpressed in a variety of tumors, could be specifically responsible for the loss of response to receptor-mediated apoptosis. RESULTS: Cotreatment of several hepatoma cell lines with the Src inhibitor PP2 potently sensitized these cells to TRAIL and CD95, dramatically decreasing effective doses of TRAIL to as low as 1 ng/ml. Remarkably, Src-inhibition did not synergize with TRAIL signaling in primary hepatocytes. Specific siRNAs showed that the effect was due to blockade of p60(c-Src) and occurred through increased recruitment of caspase 8. CONCLUSIONS: We provide evidence that p60(c-Src) is an important and effective suppressor of receptor-mediated apoptosis in hepatoma cells but not in primary human hepatocytes. Inhibition of Src sensitizes tumor cells to apoptosis and decreases effective doses of TRAIL to therapeutic concentrations.

Inhibition of c-Jun-N-terminal-kinase sensitizes tumor cells to CD95-induced apoptosis and induces G2/M cell cycle arrest.

Loss of susceptibility to apoptosis signals is a crucial step in carcinogenesis. Therefore, sensitization of tumor cells to apoptosis is a promising therapeutic strategy. c-Jun-N-terminal-kinases (JNK) have been implicated in stress-induced apoptosis, but may also contribute to survival signaling. Here we show that CD95-induced apoptosis is augmented by the JNK inhibitor SP600125 and small interfering RNA directed against JNK1/2. SP600125 potently inhibited methyl methane sulfonate-induced phosphorylation of c-Jun, but had minimal effect on apoptosis alone. In contrast, it strongly enhanced CD95-mediated apoptosis in six of eight tumor cell lines and led to a G2/M phase arrest in all cell lines. SP600125 enhanced cleavage of caspase 3 and caspase 8, the most upstream caspase in the CD95 pathway. JNK inhibition up-regulates p53 and its target genes p21Cip1/Waf1 and CD95. However, although HCT116 p53-/- cells and p21+/+ cells were less sensitive to CD95 stimulation than their p53+/+ and p21-/- counterparts, p53 and p21 were not involved in the JNK-mediated effect. JunD, which was described to be protective in tumor necrosis factor-induced apoptosis, was not regulated by JNK inhibition on the protein level. When transcription was blocked by actinomycin D, JNK inhibition still enhanced apoptosis to a comparable extent. We conclude that JNK inhibition has antitumor activity by inducing growth arrest and enhancing CD95-mediated apoptosis by a transcription-independent mechanism.