Abstract 490: Clinical improvement of symptomatic advancing chronic lymphocytic leukemia following mifepristone therapy despite normal serum levels of the immunomodulatory protein the progesterone induced blocking factor (PIBF).

Abstract

Recently a sensitive ELISA assay been created to detect serum levels of the immunomodulatory protein, the PIBF. One of the 34 kDa forms of PIBF increases markedly after exposure to progesterone (P) and inhibits natural killer (NK) cytolytic activity by stabilizing perforin granules and causes of shift from thymic helper (TH)1 to TH2 dominance thus diminishing the activity of the cellular immune system. The 34 kDa form is secreted by gamma/delta T cells and is considered a vital step in preventing immune destruction of the fetal semi-allograft. Evaluation of mRNA for PIBF and PIBF protein found that 29 of 29 human leukemia cell lines over-expressed mRNA for PIBF but only 3 of the lines expressed the PIBF protein. Adding P to the culture up-regulated PIBF protein expression whereas adding the P receptor antagonist mifepristone caused down-regulation of PIBF expression. Mifepristone treatment has been demonstrated to show significant palliative effects on a wide variety of murine and human cancers many of which are not known to be P receptor positive. The hypothesized mechanism is that these tumors either secrete PIBF or direct secretion by gamma/delta T cells in the tumor microenvironment and thus inhibit NK cell cytolytic activity. The inhibition is abrogated by inhibiting P receptors and thus a local form of P secretion by the tumor is hypothesized. The objective of this study was to determine if mifepristone will only help inhibit cancer growth in those individuals who have an increased PIBF level present in their serum. An 81 year old woman with chronic lymphocytic leukemia (CLL) started more rapid advancement and became very symptomatic. She refused chemotherapy when she almost had a lethal complication to oral chlorambucil. She requested mifepristone. Her serum PIBF level of 34.9 ng/mL was in the same range as controls without cancer. However within a month of taking 200mg daily of mifepristone orally she showed a dramatic improvement in her CLL with her white blood cell count dropping from 28,000 to 8,000. Her platelet count increased from 40,000 to 240,000 and 2 lung nodules thought to represent possible primary lung cancer (but possibly nodules from her CLL) completely disappeared on repeat CT scan. Also her energy markedly improved and her persistent cough stopped. The serum PIBF did not decrease with mifepristone therapy - 48.3 ng/mL one month later. These data demonstrated that failure to see a marked increase in serum PIBF in a patient with cancer does not predict failure to respond to mifepristone. Though mifepristone has ameliorated murine leukemia in AKR mice this is the first case report of this drug improving human leukemia. The 34-36 kDa PIBF found in cytoplasm of cancer cells may either not be secreted in the serum or may be immunologically different from serum PIBF found after P exposure. Citation Format: Jerome H. Check, Ann DiAntonio, Diane Check, Alex Jaffe, Rachael Cohen, Mojirayo Sarumi, Maya Srivastava. Clinical improvement of symptomatic advancing chronic lymphocytic leukemia following mifepristone therapy despite normal serum levels of the immunomodulatory protein the progesterone induced blocking factor (PIBF). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 490. doi:10.1158/1538-7445.AM2013-490

Progesterone and Glucocorticoid Receptor Modulator Mifepristone (RU-486) as Treatment for Advanced Cancers

“…At the time of starting mifepristone therapy, he was paralyzed from the neck down and his hands were fixed in the clenched position. He slept most of the day, and when awake, was not able to carry out conversations [43].…”

“…However, his paralysis slowly progressed to the point where he was having trouble breathing and swallowing. The mifepristone was stopped, and he died 2 weeks later [43].…”

The role of progesterone and the progesterone receptor in human reproduction and cancer

“…The authors gavaged mice with spontaneous leukemia, lung cancer, testicular cancer and prostate cancer, and found improvement in length and quality of survival compared with controls [122][123][124]. The authors subsequently published some anecdotal reports showing significant palliative effects in patients with very advanced and highly metastatic cancers, all of which were resistant to standard therapies including colon cancer, thymic cell epithelial cell cancer, transitional cell carcinoma of the renal pelvis, leiomyosarcoma, pancreatic cancer, malignant fibrous histiocytoma and acute leukemia [125][126][127]. Recently, mifepristone was shown to cross the blood-brain barrier by demonstrating an objective clinical improvement in a male with end-stage glioblastoma multiforme [128].…”

“…Recently, mifepristone was shown to cross the blood-brain barrier by demonstrating an objective clinical improvement in a male with end-stage glioblastoma multiforme [128]. In some of these aforementioned studies, there was demonstration of significant improvement on predicted length of life and marked clinical improvement [125][126][127]. These aforementioned cancers are not known to be PR+.…”