Though Pancreatic Cancer may be Resistant to Immunotherapy from Immune Checkpoint Inhibitors, it may be Sensitive to Blocking the Production of Immunoprotective Proteins Unique to Pregnancy

Abstract

Objective: Pancreatic cancer does not respond to immune checkpoint inhibitors, and therefore, it is considered a cancer that is not immunosensitive. However, even though pancreatic cancer may not produce the programmed cell death protein ligand 1 (PD-L1), it may produce immunomodulatory proteins, e.g., the progesterone-induced blocking factor (PIBF) produced by activating membrane progesterone receptors. If so, inhibition of pancreatic cancer regression and/or tumor regression may be found following treatment with a progesterone receptor modulator, e.g., mifepristone.

Methods: Mifepristone 200 mg orally daily was given to a terminal 83-year-old patient suffering from stage IV pancreatic cancer with jaundice related to bile duct destruction, mid-epigastric pain, anorexia, and marked weakness.

Results: Within 3 weeks, the jaundice was no longer present, and her pain, anorexia, fatigue, and cognition markedly improved. Unfortunately, she slipped in the shower and broke her nose and ribs. The hospital refused to allow her to take the Mifepristone because it was off-label. The cancer aggressively returned after being without mifepristone therapy for 2.5 weeks.

Conclusion: This was the second case showing marked palliative benefits to well-tolerated mifepristone. It is also the second case shown that the cancer will resume active spread if the drug is stopped for more than a week.

Introduction

This case report will discuss the potential benefit of a novel immuno/endocrine therapy for advanced pancreatic cancer, a malignancy that is generally considered immunoresistant. This manuscript will explain the difference between immune checkpoint inhibitors widely used for treating a whole variety of cancers (but not pancreatic cancer) that are directed against certain proteins e.g., programmed cell death factor 1 (PD-1) and its ligand (PD-L1) (which helps prevent cytotoxic T-cell attack of normal tissue) versus this new treatment modality aimed at suppressing immunomodulatory proteins e.g., the progesterone induced blocking factor (PIBF) which is needed for inhibiting immune rejection of the fetus. Tumor cells have surface onco-fetal antigens that should evoke immuno-destructive mechanisms by the host. These aberrant malignant cells are constantly being recognized by T-cells and are subsequently destroyed [11Smith-Garvin JE, Koretzky GA, Jordan MS. T cell activation. Annu Rev Immunol. 2009;27:591-619. doi: 10.1146/annurev.immunol.021908.132706. PMID: 19132916; PMCID: PMC2740335.]. There are various mechanisms in place to prevent the immune system from attacking normal tissue cells. One mechanism to promote immune tolerance is for normal cells to activate certain surface proteins on these T-cells, e.g., programmed cell death protein-1 (PD-1), which will dampen the destructive activity of these T-cells once activated [22Jhunjhunwala S, Hammer C, Delamarre L. Antigen presentation in cancer: insights into tumour immunogenicity and immune evasion. Nat Rev Cancer. 2021 May;21(5):298-312. doi: 10.1038/s41568-021-00339-z. Epub 2021 Mar 9. PMID: 33750922.].

One mechanism involved in allowing some cancers to evade immune surveillance and form into malignant tumors is to produce certain proteins that activate the checkpoint proteins on T-cells, thus inhibiting T-cell response against the cancer cells [33Fife BT, Bluestone JA. Control of peripheral T-cell tolerance and autoimmunity via the CTLA-4 and PD-1 pathways. Immunol Rev. 2008 Aug;224:166-82. doi: 10.1111/j.1600-065X.2008.00662.x. PMID: 18759926.]. One of these surface proteins secreted by cancer cells interacts with PD-1, which activates the PD-1 immune checkpoint protein and thus inhibits T- cell cytotoxic activity [44Pavelescu LA, Enache RM, Roşu OA, Profir M, Creţoiu SM, Gaspar BS. Predictive Biomarkers and Resistance Mechanisms of Checkpoint Inhibitors in Malignant Solid Tumors. Int J Mol Sci. 2024 Sep 6;25(17):9659. doi: 10.3390/ijms25179659. PMID: 39273605; PMCID: PMC11395316.].

The development of monoclonal antibodies against both PD-1 on the T cell surface and PD-L1 on the tumor cell surface has allowed the activation of T-cell cytotoxic anti-tumor response by blocking checkpoint activity that was suppressing T cell function. These monoclinal antibody therapies aimed to inhibit checkpoint activation have been termed immune checkpoint inhibitors (ICIs). The first FDA-approved PD-1 inhibitor was pembrolizumab, followed shortly after by nivolumab in 2014 for melanomas [44Pavelescu LA, Enache RM, Roşu OA, Profir M, Creţoiu SM, Gaspar BS. Predictive Biomarkers and Resistance Mechanisms of Checkpoint Inhibitors in Malignant Solid Tumors. Int J Mol Sci. 2024 Sep 6;25(17):9659. doi: 10.3390/ijms25179659. PMID: 39273605; PMCID: PMC11395316.]. Other ICIs directed against PD-1 include cemiplimab, dostalimab, and toripalimab [44Pavelescu LA, Enache RM, Roşu OA, Profir M, Creţoiu SM, Gaspar BS. Predictive Biomarkers and Resistance Mechanisms of Checkpoint Inhibitors in Malignant Solid Tumors. Int J Mol Sci. 2024 Sep 6;25(17):9659. doi: 10.3390/ijms25179659. PMID: 39273605; PMCID: PMC11395316.].

There are also ICIs directed against PD-L1, including atezolizumab, durvalumab, and avelumab [44Pavelescu LA, Enache RM, Roşu OA, Profir M, Creţoiu SM, Gaspar BS. Predictive Biomarkers and Resistance Mechanisms of Checkpoint Inhibitors in Malignant Solid Tumors. Int J Mol Sci. 2024 Sep 6;25(17):9659. doi: 10.3390/ijms25179659. PMID: 39273605; PMCID: PMC11395316.]. Cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) is another protein that tumors make that inhibits T-cell activation. By blocking its action with a monoclonal antibody, e.g., ipilimumab or tremelimumab, they also inhibit some types of cancer development [44Pavelescu LA, Enache RM, Roşu OA, Profir M, Creţoiu SM, Gaspar BS. Predictive Biomarkers and Resistance Mechanisms of Checkpoint Inhibitors in Malignant Solid Tumors. Int J Mol Sci. 2024 Sep 6;25(17):9659. doi: 10.3390/ijms25179659. PMID: 39273605; PMCID: PMC11395316.].

These ICIs may be effective against multiple different cancers. However, some cancers respond better to some of these ICIs than others. Some have been tested only against certain cancers, so FDA approval may be lacking for the treatment of a certain cancer by a specific ICI. However, with future studies, other cancers may eventually be approved to be treated by a given ICI. Future production of these ICIs may be influenced by various cytokines, e.g., interferon-gamma [55Tufail M, Jiang CH, Li N. Immune evasion in cancer: mechanisms and cutting-edge therapeutic approaches. Signal Transduct Target Ther. 2025 Jul 31;10(1):227. doi: 10.1038/s41392-025-02280-1. PMID: 40739089; PMCID: PMC12311175.]

Some of the approved ICIs only work in a low percentage of the types of cancers in which they were approved. There are many reasons for primary resistance, which have been summarized by Pandey and Ernstuff [66Pandey MR, Ernstoff MS. Mechanism of resistance to immune checkpoint inhibitors. Cancer Drug Resist. 2019 Jun 19;2(2):178-188. doi: 10.20517/cdr.2018.015. PMID: 35582715; PMCID: PMC8992621.]. They also explain in great detail the reasons why a given cancer may initially respond to an ICI but then develop acquired resistance [66Pandey MR, Ernstoff MS. Mechanism of resistance to immune checkpoint inhibitors. Cancer Drug Resist. 2019 Jun 19;2(2):178-188. doi: 10.20517/cdr.2018.015. PMID: 35582715; PMCID: PMC8992621.].

As mentioned previously, checkpoint proteins on T-cells are activated by proteins on normal cells to prevent immune rejection of normal autologous cells and, therefore, allow self-tolerance. Thus, it is not unexpected that ICI therapy may lead to autoimmune side effects when used as an anti-cancer therapy. They are known as immune-related adverse events (irAEs). The organ systems most involved are the skin, gastrointestinal tract, lungs, and endocrine glands [77Zoghbi M, Burk KJ, Haroun E, Saade M, Carreras MTC. Immune checkpoint inhibitor-induced diarrhea and colitis: an overview. Support Care Cancer. 2024 Sep 23;32(10):680. doi: 10.1007/s00520-024-08889-2. PMID: 39311981; PMCID: PMC11420271.,88Liu K, Wang YH, Luo N, Gong J, Wang J, Chen B. Treatment-related gastrointestinal adverse events of nivolumab plus ipilimumab in randomized clinical trials: a systematic review and meta-analysis. Future Oncol. 2023 Sep;19(27):1865-1875. doi: 10.2217/fon-2022-0615. Epub 2023 Sep 27. PMID: 37753664.]. These irAEs are sometimes so severe that treatment must be halted. Even death related to irAEs has occurred.

Unfortunately, to date, ICIs have not been very effective for pancreatic cancer [99Mukherji R, Debnath D, Hartley ML, Noel MS. The Role of Immunotherapy in Pancreatic Cancer. Curr Oncol. 2022 Sep 23;29(10):6864-6892. doi: 10.3390/curroncol29100541. PMID: 36290818; PMCID: PMC9600738.]. This resistance to not only immune therapy but even chemotherapy may be related to the ability of pancreatic ductal adenocarcinoma cells to co-opt elements of the stromal microenvironment to withstand treatment by nutrient deprivation, immune surveillance, and cytokine therapies [1010Sherman MH, Beatty GL. Tumor Microenvironment in Pancreatic Cancer Pathogenesis and Therapeutic Resistance. Annu Rev Pathol. 2023 Jan 24;18:123-148. doi: 10.1146/annurev-pathmechdis-031621-024600. Epub 2022 Sep 21. PMID: 36130070; PMCID: PMC9877114.].

The prognosis of patients with pancreatic ductal adenocarcinoma is extremely poor, partly because it is usually diagnosed at an advanced stage. Surgical treatment results in only a 44% 5-year survival if performed at an early stage. With regional involvement, the 5-year survival is only 14.7%, and with distinct metastases the 5-year survival is only 3.1% [1010Sherman MH, Beatty GL. Tumor Microenvironment in Pancreatic Cancer Pathogenesis and Therapeutic Resistance. Annu Rev Pathol. 2023 Jan 24;18:123-148. doi: 10.1146/annurev-pathmechdis-031621-024600. Epub 2022 Sep 21. PMID: 36130070; PMCID: PMC9877114.].

There is evidence that the fetal semi-allograft may use different or additional immunosuppressive proteins than PD-L1 or CTLA-4 to inhibit cellular immune reaction, which may also be utilized by cancer cells to evade immune surveillance [1111Check JH, Nazari P, Goldberg J, Yuen W, Angotti D. A model for potential tumor immunotherapy based on knowledge of immune mechanisms responsible for spontaneous abortion. Med Hypotheses. 2001 Sep;57(3):337-43. doi: 10.1054/mehy.2001.1333. PMID: 11516226.]. These immunomodulatory proteins seems to require activation of membrane P receptors (mPRS) for their production [1212Check JH, Ganpo NN. The role of membrane progesterone receptor-associated proteins in gynecological and reproductive disorders, and cancers: an editor’s historical perspective, Part 1: Molecular Aspects. J Sex Health Reprod Med. 2026; 2(1): 1-6. doi: doi.org/10.61440/JSHRM.2026.v2.3]. Thus, drugs that block mPRs and suppress the production of these immunomodulatory proteins could have potential in treating various malignancies [1313Check JH, Dix E, Sansoucie L. Support for the hypothesis that successful immunotherapy of various cancers can be achieved by inhibiting a progesterone associated immunomodulatory protein. Med Hypotheses. 2009 Jan;72(1):87-90. doi: 10.1016/j.mehy.2008.05.042. Epub 2008 Oct 7. PMID: 18842348.]. Though it may seem counterintuitive, cancers that are initially positive for the nuclear PR (nPR) may not respond as well as those cancers devoid of the nPR because there seem to be nPR-derived substances that promote immune destruction of cancer cells [1414Check JH, Check D. New Insights as to Why Progesterone Receptor Modulators, such as Mifepristone, Seem to Be More Effective in Treating Cancers that Are Devoid of the Classical Nuclear Progesterone Receptor. Anticancer Res. 2021 Dec;41(12):5873-5880. doi: 10.21873/anticanres.15407. PMID: 34848442.].

The only progesterone receptor modulator that was commercially available at the time that research was trying to determine if PR antagonists could inhibit cancers devoid of the nPR was mifepristone. Many cancer cell line studies and animal studies were able to demonstrate that the PR modulator mifepristone could inhibit the production of one of those key mPR-induced proteins called the progesterone-induced blocking factor (PIBF) [1515Srivastava MD, Thomas A, Srivastava BI, Check JH. Expression and modulation of progesterone induced blocking factor (PIBF) and innate immune factors in human leukemia cell lines by progesterone and mifepristone. Leuk Lymphoma. 2007 Aug;48(8):1610-7. doi: 10.1080/10428190701471999. PMID: 17701593.]. Unfortunately, because the approved use of the 200mg tablet of mifepristone was as an abortifacient, related to the sensitivity of many people not approving voluntary termination of a healthy baby, the United States Food and Drug Administration (FDA), and many governmental agencies in other countries, made it very difficult to obtain mifepristone for anyone other than a licensed abortionist. Based on the positive cancer cell line data and animal experiments on spontaneous murine cancer, the FDA was willing to allow a physician to prescribe mifepristone for patients with very advanced cancers that had no more treatment options [1616Check JH, Cohen R. The role of progesterone and the progesterone receptor in human reproduction and cancer. Expert Rev Endocrinol Metab. 2013 Sep;8(5):469-484. doi: 10.1586/17446651.2013.827380. PMID: 30754194.]. Each patient thus required a compassionate use investigational new drug approval (IND) [1616Check JH, Cohen R. The role of progesterone and the progesterone receptor in human reproduction and cancer. Expert Rev Endocrinol Metab. 2013 Sep;8(5):469-484. doi: 10.1586/17446651.2013.827380. PMID: 30754194.].

The first published case report of very successful prolongation of a good quality life following daily single agent treatment with oral 200 mg mifepristone for a cancer devoid of the nPR was a woman with widely metastatic colon cancer in 2009 (even before the first publications of using ICIs) [1717Check JH, Dix E, Sansoucie L, Check D. Mifepristone may halt progression of extensively metastatic human adenocarcinoma of the colon - case report. Anticancer Res. 2009 May;29(5):1611-3. PMID: 19443374.]. Adenocarcinoma of the colon would be considered a malignancy that is also sensitive to ICIs. There have been many subsequent case reports since that time until the present finding marked palliative benefits with extension of life in patients with a variety of different types of cancers [1818Check JH, Check DL. The role of progesterone and the progesterone receptor in cancer: progress in the last 5 years. Expert Rev Endocrinol Metab. 2023 Jan;18(1):5-18. doi: 10.1080/17446651.2023.2166487. Epub 2023 Jan 16. PMID: 36647582.]. An up-to-date summary in table form of advanced cancers showing clinical improvement following treatment with single-agent mifepristone has been recently published [1919Check JH, Check DL, Ganpo-Nkewnkwa N. Marked Palliative Benefits Seen With Treatment of Very Advanced Breast Cancer With the Progesterone Receptor Modulator Mifepristone. Anticancer Res. 2026 Feb;46(2):1153-1165. doi: 10.21873/anticanres.18018. PMID: 41617454.]. There has been a small series published showing a good quality 66.7% overall 5-year survival in patients with terminal small cell and non-small cell lung cancer treated with oral single agent mifepristone [2020Check JH, Check DL, Wilson C. Good Quality 66.7% 5-year Overall Survival in Terminal Lung Cancer Patients Treated With Mifepristone. Anticancer Res. 2025 Dec;45(12):5785-5798. doi: 10.21873/anticanres.17911. PMID: 41318113.].

One of the case reports mentioned showed that mifepristone proved highly effective for a patient with very end-stage pancreatic cancer [2121Check JH, Check D, Srivastava MD, Poretta T, Aikins JK. Treatment With Mifepristone Allows a Patient With End-stage Pancreatic Cancer in Hospice on a Morphine Drip to Restore a Decent Quality of Life. Anticancer Res. 2020 Dec;40(12):6997-7001. doi: 10.21873/anticanres.14724. Epub 2020 Dec 7. PMID: 33288594.]. This would suggest that, whereas pancreatic cancer may be resistant to ICI therapy, it may be sensitive to PR antagonists that suppress PIBF and possibly other mPR-associated immunomodulatory proteins.

The question is whether the aforementioned case of pancreatic cancer is a rare exception or possibly the rule. A case is presented supporting the conclusion that pancreatic cancer may be sensitive to PR antagonists and thus be immunosensitive to some therapies activating immune activity that has been inhibited by secretions from the tumor cells. The term “immunotherapy” usually refers to monoclonal antibody therapy directed against checkpoint proteins or their ligands or other pathways used for cancer cell proliferation, invasion of normal tissue, and evasion of immune surveillance. Though PR antagonist therapy theoretically leads to activation of innate immune activity, leading to the destruction of cancer cells and inhibition of metastatic spread, a more appropriate term may be immunoendocrine therapy [2222Check JH. Novel immunoendocrine therapy of advanced cancers of all types opens a new medical field for clinical and research endocrinologists. Am J Biomed Sci Res. 2024; 23(1): 86-98.].

Case report

An 83-year-old Asian female physician developed fatigue and mid-epigastric pain, and thought it was just a viral infection. However, after two weeks, her symptoms intensified, and she noticed that her urine was dark, so she consulted her physician. She was clearly jaundiced, not as noticeably by skin color change, but had yellowish sclera. Blood tests confirmed that she had hyperbilirubinemia and an increase in liver enzymes. Positron emission tomography (PET) scan identified a pancreatic mass with evidence of metastatic lesions to her liver and lungs.

Her family history was important in that one of her brothers died at age 65 with advanced pancreatic cancer. Her past medical history was important in that she had 4 unsuccessful surgeries for lower back degenerative disk disease, which caused balance issues leading to several falls with minor but no serious injuries for the 2 years prior to admission to the hospital. She was admitted mostly to receive intravenous fluids for severe dehydration. Consultations from various medical specialists advised her that there were no reasonable treatment options and that she was terminal. They strongly recommended hospice. Thus, she refused the option of a Whipple procedure, so the diagnosis of adenocarcinoma of the exocrine pancreas was not confirmed; nevertheless, based on the clinical and laboratory findings and radiographic evidence, all consultants in the hospital concluded that she had pancreatic cancer.

She was discharged with opiates for pain and advised to consult home hospice and prepare for death with a minimum degree of suffering. Instead, she consulted our practice to discuss treatment with the progesterone receptor antagonist mifepristone. She had searched the literature and found a very positive case report of a man with terminal pancreatic cancer responding very well to single-agent mifepristone 200 mg orally per day [2121Check JH, Check D, Srivastava MD, Poretta T, Aikins JK. Treatment With Mifepristone Allows a Patient With End-stage Pancreatic Cancer in Hospice on a Morphine Drip to Restore a Decent Quality of Life. Anticancer Res. 2020 Dec;40(12):6997-7001. doi: 10.21873/anticanres.14724. Epub 2020 Dec 7. PMID: 33288594.].

Within 3 weeks, she was feeling much better. Her mental faculties returned to normal. She had a lot more energy. She had very little pain, which was actually the same in her back that she experienced for the last 2 years related to degenerative disk disease. The more severe abdominal pain was gone. Her appetite improved, and food started tasting normal again. She continued daily exercise with walking. The amount of pain did not require opiates, and she only occasionally took non-steroidal anti-inflammatory drugs. Her urine color was now normal. She lived alone in a retirement condominium that had no medical facilities or nursing care. Unfortunately, after almost one month of mifepristone, she slipped in the shower, and it is unclear how long she remained there before being found by a neighbor. She was taken to the emergency room and was found to have fractured her nose and ribs. She remained in the hospital for intravenous fluids and observation for head injury and multiple consults from various specialists again, i.e., surgery, oncology, hospice, social services, and internal medicine.

She refused all other suggested options and just wanted to resume taking her Mifepristone pills. They refused to give it to her because it was an off-label use against hospital policy. She remained off mifepristone for 6 days, and she started to deteriorate again, especially with cognitive function and energy. Thus, instead of leaving the hospital and resuming mifepristone before it was too late (or maybe it was already), she agreed to go to the rehabilitation center, which lasted another 12 days. We thought that the rehabilitation center would allow her to take the Mifepristone again, but they also refused.

Thus, she was off the Mifepristone for 2.5 weeks, and there was evidence of rapid return of end-stage cancer. She was now having difficulty swallowing pills, so her power of attorney granted after consultation with us decided to proceed with hospice and help her end her life peacefully. We had advised her prior to admission that it has been our experience that the drug must be taken continuously, or rapid return and progression of the cancer would occur. Unfortunately, her cognitive state had declined, so she was not able to be her own self-advocate and leave the rehab center and return home so that she could resume her 200mg oral mifepristone tablet. It was unlikely that having stopped therapy so long that it would be effective anymore. The decision not to restart mifepristone therapy, but instead to enter hospice, was influenced by her difficulty swallowing pills and the fact that no caretaker could try to administer the drug rectally.

Discussion

Our experience with treating cancer with mifepristone has generally been only in very terminal patients, except one patient who had multifocal renal cell carcinoma, where the FDA granted permission to use it on him because of the adverse consequences of the recommended treatment at that time, which was bilateral nephrectomy followed by hemodialysis [2222Check JH. Novel immunoendocrine therapy of advanced cancers of all types opens a new medical field for clinical and research endocrinologists. Am J Biomed Sci Res. 2024; 23(1): 86-98.,2323Check DL, Check JH, Poretta T. Conservative laparoscopic surgery plus mifepristone for treating multifocal renal cell carcinoma. Cancer Sci Res. 2020; 3(2): 1-4.]. He is now 25 years past diagnosis.

Though all other patients were terminal and had no other treatment options, the large majority of these patients demonstrated significant palliative benefits and frequently considerable extension of life [2222Check JH. Novel immunoendocrine therapy of advanced cancers of all types opens a new medical field for clinical and research endocrinologists. Am J Biomed Sci Res. 2024; 23(1): 86-98.].

Frequently, the palliative benefits occur before there is any radiographic evidence of tumor regression, though over time, our previous patients have shown considerable tumor regression, and in a minority, even radiographic evidence of total tumor regression. In this patient’s case report, a CT scan was not performed until 10 days off the drug, and by that time, there was no evidence of any tumor regression. As seen in the previous case report of pancreatic cancer, and our experience when patients who were clinically doing well, and where there had been observed significant tumor regression, but not complete remission, and where the patient’s clinical oncologist opted to temporarily stop mifepristone in favor of a new clinical trial, if the new drug was not effective, that one finds accelerated return and advancement of the cancer and quick death. Thus, in the case described, we do not know if her clinical improvement was associated with radiographic evidence of tumor regression or not while she was taking the mifepristone. Many of these patients who were typically elderly died from other co-morbidities and not the cancer per se [2222Check JH. Novel immunoendocrine therapy of advanced cancers of all types opens a new medical field for clinical and research endocrinologists. Am J Biomed Sci Res. 2024; 23(1): 86-98.]. The various cancer types that we have treated with single-agent mifepristone and their references are found in Tables 1,2 in a recent publication on treating very advanced breast cancer with mifepristone [1919Check JH, Check DL, Ganpo-Nkewnkwa N. Marked Palliative Benefits Seen With Treatment of Very Advanced Breast Cancer With the Progesterone Receptor Modulator Mifepristone. Anticancer Res. 2026 Feb;46(2):1153-1165. doi: 10.21873/anticanres.18018. PMID: 41617454.]. In addition to renal cell cancer, pancreatic cancer, and colon cancer, positive benefits have been found in thymic epithelial cell, leiomyosarcoma, transitional cell carcinoma of the renal pelvis, glioblastoma multiforme stage IV, fibroblastic histiosarcoma, fibroblastic osteosarcoma, small cell and non-small cell lung, urothelial, and breast cancer [1919Check JH, Check DL, Ganpo-Nkewnkwa N. Marked Palliative Benefits Seen With Treatment of Very Advanced Breast Cancer With the Progesterone Receptor Modulator Mifepristone. Anticancer Res. 2026 Feb;46(2):1153-1165. doi: 10.21873/anticanres.18018. PMID: 41617454.,2222Check JH. Novel immunoendocrine therapy of advanced cancers of all types opens a new medical field for clinical and research endocrinologists. Am J Biomed Sci Res. 2024; 23(1): 86-98.]. One case not included in the table was a woman with adult B-cell acute lymphocytic leukemia [2424Check JH. Adult B-cell acute lymphocytic leukemia associated with osteolysis, but normal hematologic parameters – rare case or related to treatment with mifepristone. Int J Clin Med Case Stud. 2025; 2(1):1016.]. These cases, with the exception of one, would be considered far too advanced to be included in clinical trials. We have reported every case we treated unless they died within one week. To reiterate, all patients showed some improvement.

We caution patients not to stop the mifepristone because it will rapidly return and likely lead to a quick death. In some instances, death was from maladies unrelated to the cancer. Even in those cases where the tumor was so extensive that it was likely to eventually cause death, we have never observed rapid progression while patients have persisted in taking the drug daily. The aforementioned case of pancreatic cancer was within 2 weeks of death before treatment with mifepristone, and the patient was feeling great 9 months later. He stopped the drug because he could no longer afford it [2121Check JH, Check D, Srivastava MD, Poretta T, Aikins JK. Treatment With Mifepristone Allows a Patient With End-stage Pancreatic Cancer in Hospice on a Morphine Drip to Restore a Decent Quality of Life. Anticancer Res. 2020 Dec;40(12):6997-7001. doi: 10.21873/anticanres.14724. Epub 2020 Dec 7. PMID: 33288594.,2222Check JH. Novel immunoendocrine therapy of advanced cancers of all types opens a new medical field for clinical and research endocrinologists. Am J Biomed Sci Res. 2024; 23(1): 86-98.]. Though in some countries mifepristone costs only about one dollar per pill, in the United States it costs 42 dollars per pill. Though feeling great at that time when the aforementioned patient with pancreatic cancer stopped the mifepristone, he died two weeks later. Even at 42 dollars per pill, a year of taking Mifepristone would cost $15,000. Compare that to $100,000 to one million dollars per year for ICIs. It is true that once approved, insurance companies pay the majority of the cost of ICIs, but this greatly contributes to the huge expense of buying health care insurance today.

Mifepristone has been effective even in patients who do not respond to ICIs [2525Check JH, Check D, Poretta T. Mifepristone Extends Both Length and Quality of Life in a Patient With Advanced Non-small Cell Lung Cancer that Has Progressed Despite Chemotherapy and a Check-point Inhibitor. Anticancer Res. 2019 Apr;39(4):1923-1926. doi: 10.21873/anticanres.13301. PMID: 30952734.]. In some instances, one will see the complete disappearance of all metastatic lesions, e.g., a very moribund patient with small cell lung cancer [2626Check JH, Check DL, Dougherty MP. Progesterone receptor antagonists – a novel treatment for severe hyponatremia from the endocrine paraneoplastic syndrome. J Endocrinol Res. 2021; 3:40-43.]. However, in the majority of instances, though the patient feels so much better and usually can resume a productive life, tumor burden, especially metastatic lesions, is significantly decreased; frequently, some lesions persist, but they remain stable. Sometimes, after a couple of years, the primary lesion may start growing slowly. We advise patients to stay on the mifepristone and not switch to another drug. We explain that the increase in size is not the beginning of the rapid spread. One man with terminal stage IV non-small cell lung cancer, after 2.5 years, began showing signs of slow growth of his primary lung lesion. His oncologist suggested stopping the mifepristone and trying nivolumab even though the tumor was negative for the PD-L1 marker. We advised him to stay on the Mifepristone. He lived another 3 years without much cancer progression but succumbed to pneumonia during the COVID pandemic [2222Check JH. Novel immunoendocrine therapy of advanced cancers of all types opens a new medical field for clinical and research endocrinologists. Am J Biomed Sci Res. 2024; 23(1): 86-98.,2727Check DL, Check JH. Significant palliative benefits of single-agent mifepristone for advanced lung cancer that previously failed standard therapy. Med Clin Sci. 2019; 1(2): 1-5.].

Another reason why some patients stopped their mifepristone therapy was that, despite our admonition about stopping the drug, their oncologists, still seeing some lesions present, convinced the patient to stop the drug temporarily and enter a clinical trial with an experimental drug. If the trial drug was not effective, they could resume the mifepristone. One man with very advanced fibroblastic osteosarcoma was alive and doing well after 5 years. He stopped the Mifepristone in favor of a new drug evaluated for a clinical trial. He died 2 weeks later with a rapid spread of his cancer before he could resume the mifepristone [2222Check JH. Novel immunoendocrine therapy of advanced cancers of all types opens a new medical field for clinical and research endocrinologists. Am J Biomed Sci Res. 2024; 23(1): 86-98.,2828Check JH, Check D, Poretta T, Wilson C. Palliative Benefits of Oral Mifepristone for the Treatment of Metastatic Fibroblastic Osteosarcoma. Anticancer Res. 2021 Apr;41(4):2111-2115. doi: 10.21873/anticanres.14982. PMID: 33813421.].

Actually, we did treat a physician’s wife with mifepristone, who had very advanced pancreatic cancer, who was still having a significant degree of pain despite opiates given to her through hospice. After 2 weeks of taking mifepristone, her husband advised our center that her pain was so much better that she was hardly using any opiates. However, her previous cancer center called and advised her that she would qualify for a phase II drug trial. They stopped Mifepristone, started the new drug, which proved to be cardiotoxic, and she died 2 days later while taking the new drug [2929Check JH, Dix E, Cohen R, Check D, Wilson C. Efficacy of the progesterone receptor antagonist mifepristone for palliative therapy of patients with a variety of advanced cancer types. Anticancer Res. 2010 Feb;30(2):623-8. PMID: 20332480.].

We wish that we could be reporting in this present case report a patient with advanced pancreatic cancer with a 5-year survival. Instead, consistent with our previous experience with treating cancer with mifepristone, this patient represents another case of mifepristone showing significant palliation in a patient with a deadly cancer with great morbidity. This illustrates another reason why some patients stop the drug, i.e., a need for a hospital admission, for a non-cancer cause, but the hospital refuses to allow the patient to be administered the mifepristone because it is an off-label use of the drug. Also, following the usual “standard of care,” the physicians involved in the patient described in this case report, unaware of the benefits of mifepristone, advised her to go to a rehabilitation center, causing her to be further removed from taking the mifepristone. This led to her death from rapidly advancing pancreatic cancer.

Finally, there is evidence that, in the low dosage of mifepristone used, while mifepristone suppresses PIBF, it may actually increase the progesterone receptor membrane component-1 protein (PGRMC-1). Thus, we hope that this case report may generate interest in a pharmaceutical company to develop a better PR modulator than mifepristone that could suppress not just PIBF secretion but also PGRMC-1 [3030Check JH, Check D, Neumann B. Future directions to explore to develop ideal anti-cancer progesterone receptor modulators. Cancer Sci Res. 2023; 6(1): 1-8.,3131Check JH, Check DL. A Hypothetical Model Suggesting Some Possible Ways That the Progesterone Receptor May Be Involved in Cancer Proliferation. Int J Mol Sci. 2021 Nov 16;22(22):12351. doi: 10.3390/ijms222212351. PMID: 34830233; PMCID: PMC8621132.].

Conclusion

Many physicians will not be convinced of the efficacy of a new drug therapy unless there is a clinical trial that is sufficiently powered, showing efficacy. With many cancers showing sensitivity to ICIs, it would be hard to compete with clinical trials set up by pharmaceutical companies, especially considering the considerable remuneration to hospitals for conducting these trials. Pancreatic ductal adenocarcinoma is considered to be immunoresistant and also resistant to chemotherapy and drugs aimed to suppress certain targeted molecular pathways. Based on our anecdotal experience, in addition to this case reported, we suspect that whereas pancreatic cancer may be resistant to ICIs (perhaps lacking the PD-L1 protein), it may well require mPR-associated immunomodulatory proteins to spread that are also required during pregnancy to allow the fetal CIRplacental semi-allograft to evade immunosurveillance. Thus, the hope is that this case report will generate interest in the oncology community to try mifepristone in a larger series to either corroborate or refute the benefits of this potential therapy for pancreatic cancer. However, one could argue that maybe in this case, in contrast to the previous case that we have published, the continuation of the mifepristone may have only provided short-term palliative benefits, even if she had fallen with breaking her ribs rather than sudden cessation of the drug. It is hoped that this case report will not only encourage clinicians to establish clinical trials for pancreatic cancer, but also for other cancers as well. It is equally hoped that the case will generate interest in the scientists to further explore the role of mPRs in cancer, and hopefully find other immunomodulatory proteins present only in the pregnant state that are used by malignant tumors to proliferate, invade normal tissue, and evade immune surveillance. This could lead to the potential of developing new effective anti-cancer drugs by pharmaceutical companies that have much less toxicity than present anti-cancer agents because they target a pathway only needed in pregnancy, but not in the non-pregnancy state. It is possible that future research could confirm the efficacy of the therapy but yet find that the hypothetical inhibition of PIBF is not the main mechanism of action.

Study approval

The use of mifepristone to treat advanced cancers of all types has been approved by the Western Institutional Review Board (protocol number 20121249, CIR110). The patient signed an informed consent. She was made fully aware of the nature of the drug and potential side effects and benefits before signing a consent form.

Acknowledgement

Because this is a case report, we tried to keep it as clinical as possible and limit the number of references. We would like to acknowledge the pioneer studies performed by Dr. Julia Szekeres-Bartho and her colleagues, e.g., Dr. M Lachman and Dr. B Polgar from Hungary. Though they did not have any input in this case report, we believe that their previous scientific studies should be noted. Many of their studies are referenced in our own references cited in this manuscript, especially for those scientists interested in the molecular biology of PIBF.

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Check JH, DiAntonio A. Though Pancreatic Cancer may be Resistant to Immunotherapy from Immune Checkpoint Inhibitors, it may be Sensitive to Blocking the Production of Immunoprotective Proteins Unique to Pregnancy. IgMin Res. April 10, 2026; 4(4): 110-115. IgMin ID: igmin338; DOI:10.61927/igmin338; Available at: igmin.link/p338

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10 Mar, 2026

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08 Apr, 2026

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10 Apr, 2026

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