Synchronization of chemotherapy to the anti-tumor immune cycle

Location: Royal Women’s Hospital in Melbourne (Australia) & University Hospital of Leuven (Belgium)
Collaboration: Prof. Dr. Michael Quinn (Australia) & Prof. Dr. Amant (Belgium) & Martin Ashdown (responsible scientist - Australia)

 

Cancer patients often show signs of an activated anti-tumor immune response with a strong anti-tumor capacity, but regulatory mechanisms induced by the tumor cells are preventing the immune system from really attacking the tumor. One of the regulatory mechanisms consists of a specialized cell type, regulatory T cells, capable of suppressing immune responses. Moreover, it was found that the ongoing anti-tumor immune response in cancer patients follows a continuous cyclical pattern, where immune stimulation is followed by activation of regulatory mechanisms and suppression of the immune response. This so-called “immune cycle” can be identified by frequently dosing highly sensitive CRP (hs-CRP) in the blood of the patients.

At high doses, chemotherapeutic agents mainly have a direct cytotoxic effect on tumor cells, but it has been described that, at lower doses, certain chemotherapeutics such as cyclophosphamide mainly exert their function through immunomodulatory and anti-angiogenic effects. The immunomodulatory effect is thought to be mediated through depletion and/or inactivation of regulatory T cells.

In this phase II trial, coordinated by Prof. Dr. Michael Quinn from the Royal Women’s Hospital in Melbourne (Australia), it was hypothesized that administration of low dose cyclophosphamide in the stage of the immune cycle when regulatory mechanisms are activated and most sensitive to chemotherapy will augment the efficacy of cyclophosphamide and thereby improve patient outcomes. To this end, patients with ovarian or endometrial carcinoma had frequent blood drawings over a 2 week period to identify the immune cycle followed by low dose oral cyclophosphamide treatment at certain stages of the immune cycle. This clinical trial was performed at the Royal Women’s Hospital in Melbourne (Australia) and at the University Hospital of Leuven (Belgium)  and is put on hold due to disappointing clinical results.  Collected patient samples are currently analysed in detail in Belgium and Australia to elucidate the effect of cyclophosphamide on immune and clinical parameters.