Immunotherapy for heart failure

World Congress of Cardiology Report - Heart failure (HF) is a complex, progressive clinical syndrome that can result from any structural or functional cardiac disorder, such as coronary artery disease or hypertension (high blood pressure), which impairs the ability of the heart to function properly as a pump.

As a result of this pump dysfunction, a variety of body mechanisms are activated in an attempt to compensate for this defect. Multiple systems within the body, including the neurohormonal system and the immune system, respond to the HF state. Accumulating evidence indicates that inflammatory cytokines (immune response mediators) play a pathogenic role in the progression of HF by impairing the ability of the heart to contract, inducing excessive hypertrophy (enlargement), and promoting cell death or fibrosis (the formation of fibrous tissue). These mechanisms contribute to the destructive cycle of myocardial (heart muscle) remodeling that is characteristic of chronic heart failure.

The primary objective of the ACCLAIM study was to evaluate the effects of Celacade immunotherapy on the composite endpoint of mortality or cardiovascular (CV) hospitalization in patients with chronic HF. ACCLAIM stands for Advanced Chronic Heart Failure Clinical Assessment of Immune Modulation Therapy.

Immunotherapy using the Celacade System is a novel non-drug treatment strategy that targets inflammatory mechanisms contributing to progression of chronic HF not yet addressed by current therapies. This form of immunotherapy exploits the anti-inflammatory response to cells undergoing apoptosis (programmed cell death). The physiological response of the recipient's immune system to apoptotic cells results in a decrease in inflammatory cytokines, and up-regulation of anti-inflammatory cytokines. This combined effect may be especially beneficial to patients with chronic HF, since the inflammation associated with this syndrome reflects an imbalance of the two opposing arms of the cytokine network.

Celacade immunotherapy has been shown experimentally to down-regulate pro-inflammatory cytokines and increase anti-inflammatory cytokines. We have previously shown, in a feasibility study of subjects with moderate to severe HF, that active treatment significantly reduced mortality and hospitalization. Moreover, in a recently completed study of 553 patients with atherosclerosis, this form of immunotherapy resulted in a marked reduction in the inflammatory marker hs-CRP.

The ACCLAIM study enrolled over 2,400 subjects at 177 sites in the US, Canada, Germany, Norway, Denmark, Poland, and Israel. ACCLAIM was the largest trial in HF ever conducted to evaluate a therapy targetting inflammation. At baseline, all subjects were receiving optimal standard therapy for HF including ACE inhibitors or angiotensin receptor blockers, beta-blockers, and aldosterone blocking agents as tolerated.

Immunotherapy using the Celacade System involves the ex vivo (outside the body) treatment of a 10mL sample of a patient's own (autologous) whole blood with controlled oxidative stress and subsequent intramuscular (IM) administration of the treated sample. We hypothesize that oxidative stress, a factor known to initiate apoptosis in white cells, commits the treated cells to undergo apoptosis following IM administration. Within the muscle tissue, the treated cells interact with specific immune system cells (antigen presenting cells) and elicit a systemic anti-inflammatory response.

Subjects were randomly (1:1) allocated to receive active treatment or placebo (sham treatment). Both active and placebo groups were well balanced at baseline. All subjects received treatments on Days 1, 2, and 14, and then every 28 days thereafter until the end of study, or a minimum of 22 weeks. Neither the subjects nor their doctors knew whether they were receiving real or placebo treatment (double-blind).

Our results show that although the ACCLAIM trial of Celacade immunotherapy did not meet its primary endpoint of reducing the risk of the composite of mortality or CV hospitalization, pre-specified subgroup analysis provided evidence that Celacade immunotherapy significantly reduced this risk in subjects who had not reached more advanced stages of HF.

For example, in the 689 NYHA class II patients in the study, Celacade immunotherapy reduced the risk of mortality or CV hospitalization by 39% (P=0.0003). Additional exploratory analysis in combined subgroups totaling over 70% of ACCLAIM study subjects indicated that Celacade immunotherapy was significantly more beneficial than placebo in reducing risk of mortality or morbidity.

Celacade immunotherapy was safe and well tolerated, and there was no evidence of detrimental effects on blood pressure and heart rate when used in combination with standard therapy (including vasoactive neurohormonal antagonists). Further, there was no difference in infection-related adverse events as compared to placebo, and no evidence of tolerability issues in subjects with other health problems in addition to HF.

In conclusion, the ACCLAIM trial findings support the hypothesis that inflammation participates in the progression of the HF syndrome. More importantly, the ACCLAIM trial provides evidence that Celacade immunotherapy is effective in patients who have not reached more advanced stages of heart failure, supporting the concept that exploiting the physiological anti-inflammatory response to cells undergoing apoptosis has substantial therapeutic potential. Finally, the ACCLAIM results provide a strong basis for moving forward with a confirmatory study to definitively assess the clinical utility of Celacade in this patient population.


The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of News Medical.
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