Alternative Pancreatic Cancer Treatment

   Alternative Pancreatic Cancer Treatment

Letter to the Editor, Townsend Letter for Doctors

Editor,

Survival rates for cancer of the head of the pancreas are poor. Unresectable patients live about 6 months.1 During the past two years we have been involved in the care of a patient with pancreatic cancer. The patient has had unexpectedly positive results. Knowing full well that anecdotes do not replace prospective trials, her treatment history and outcome may still be of interest to health care providers based on the fact that she has responded well in spite of an exceedingly poor prognosis and in light of the natural history of pancreatic cancer. Her case also provides insight into the potential benefits of using multiple modalities in the treatment of advanced cancers.

The Case:

The 64 y.o. white female presented to her family physician on March 15, 2001 with complaints of dizzy spells, stomach pain and a "swollen stomach." On April 30, 2001, a first CT scan revealed a 5.5 X 5.0 cm mass in the head of the pancreas. Two weeks later, a second CT scan confirmed a 5.6 cm mass on the head of the pancreas, characteristic of pancreatic cancer. Another 2 weeks later pathology of an endoscopic biopsy revealed adenocarcinoma of the head of the pancreas. The patient was told to "get her affairs in order within the next 3-4 weeks." No treatment was offered at that time. The patient and her husband traveled to another city for second opinion a few weeks later. She was offered 4 treatment options; 1) Gemcitabine, 2) 5FU+Leukovorin, 3) an experimental chemotherapeutic agent and 4) no treatment. By the beginning of July, 2001 another CT scan revealed lung and liver metastases in addition to the pancreatic mass. One day following this scan on July 6, 2001, the patient began a 6-week chemotherapy protocol with Gemzar. The doctor would not allow radiation therapy in addition to the chemotherapy. By August 6, 2001, the 4th chemotherapy treatment was administered. The chemotherapy regimen was ended after 4 weeks due the intolerable side effects. Some of these side effects causing a poor quality of life included chills every 3-4 hours and body temperatures up to 103 degrees resulting in no quality of life. At this time another CT scan was taken and showed that the lesions were still present at approximately their initial sizes.

Two weeks after stopping the Gemzar, the patient began 5FU+Leukovorin. In addition to this chemotherapeutic regimen, the patient also underwent 27 "funnel" radiation treatments daily to treat the liver and lungs metastases. While receiving the chemotherapy and radiation treatments, the patient learned about the IAT in Freeport, Bahamas. On September 11, 2001, the chemotherapy and radiation was suspended. 4 days later the patient began immunoaugmentive therapy at the IAT clinic in Freeport Bahamas. The therapy was comprised of administering sera containing naturally occurring proteins to trigger a reaction to kill tumor cells. The sera are made from human serum protein components (immuno-globulin serum antibodies and alpha 2 macro-globulin deblocking factor) derived from volunteer donors without neoplastic disease, and of tumor complement factor derived from human sera of people with malignancies.

After 1 month of IAT treatment, the patient started on a 12-week treatment comprised of one weekly intradermal injection of heat shock proteins linked to tumor antigen, one weekly intradermal injection of tumor antigen, and twice weekly subcutaneous injections of natural low-dose natural cytokines (collectively referred to as ITL immune therapy). At the same time the patient was started on ImmKine (250 mg capsules, 3 2 x per day) and C-Statin (250 mg capsules, 3 2 x per day). ImmKine is an immune stimulant isolated from bacterial cell walls that induces the production of interleukin 12. Interleukin 12 induces downstream production of anti-angiogenic cytokines. C-Statin is an angiogenesis inhibitor derived from the plant, Convolvulus arvensis, also known as Field bindweed.

On October 29th, 2001 a CT scan showed a 2.0 cm mass in the head of the pancreas and resolution of the lung and liver metastases. In mid-January, 2002 the patient returned home from IAT and restarted the 5FU+Leucovorin treatments. Another CT scan was performed one week after arriving home showed the pancreatic mass 2.5 cm.

On April 1, 2002 the patient started twice weekly intravenous infusions of 50 grams of vitamin C in 500 cc sterile water. By mid-May, a CT scan showed the pancreatic mass was reduced to less than 2.0 cm. No liver or lung lesions were visible. The vitamin C infusions were discontinued in August, 2002. The patient continued on daily immunoaugmentive therapy at home.

A recent CT scan in April, 2003 revealed a 1 cm pancreatic mass with an appearance consistent with a cyst. The patient continues to do well as of this writing (February 4, 2004), more than 34 months after becoming symptomatic and 35 months after diagnosis.

1. Ginsberg GG. New developments in pancreatic cancer. Semin Gastrointest Dis 2000 Jul;11(3):162-7

ABSTRACTS OF ARTICLES ABOUT IMMUNE THERAPY FOR PANCREATIC CANCER

MUC1-specific CTLs are non-functional within a pancreatic tumor microenvironment. Mukherjee P, Ginardi AR, Madsen CS, Tinder TL, Jacobs F, Parker J, Agrawal B, Longenecker BM, Gendler SJ. Glycoconj J. 2001 Nov-Dec;18(11-12):931-42. Department of Biochemistry and Molecular Biology, Mayo Clinic Scottsdale, Scottsdale, AZ 85259, USA.

Pancreatic cancer is a highly aggressive, treatment refractory disease and is the fourth leading cause of death in the United States. In humans, 90% of pancreatic adenocarcinomas over-express altered forms of a tumor-associated antigen, MUC1 (an epithelial mucin glycoprotein), which is a target for immunotherapy. Using a clinically relevant mouse model of pancreas cancer that demonstrates peripheral and central tolerance to human MUC1 and develops spontaneous tumors of the pancreas, we have previously reported the presence of functionally active, low affinity, MUC1-specific precursor cytotoxic T cells (pCTLs). Hypothesis for this study is that MUC1-based immunization may enhance the low level MUC1-specific immunity that may lead to an effective anti-tumor response. Data demonstrate that MUC1 peptide-based immunization elicits mature MUC1-specific CTLs in the peripheral lymphoid organs. The mature CTLs secrete IFN-gamma and are cytolytic against MUC1-expressing tumor cells in vitro. However, active CTLs that infiltrate the pancreas tumor microenvironment become cytolytically anergic and are tolerized to MUC1 antigen, allowing the tumor to grow. We demonstrate that the CTL tolerance could be reversed at least in vitro with the use of anti-CD40 co-stimulation. The pancreas tumor cells secrete immunosuppressive cytokines, including IL-10 and TGF-beta that are partly responsible for the down-regulation of CTL activity. In addition, they down-regulate their MHC class I molecules to avoid immune recognition. CD4+ CD25+ T regulatory cells, which secrete IL-10, were also found in the tumor environment. Together these data indicate the use of several immune evasion mechanisms by tumor cells to evade CTL killing. Thus altering the tumor microenvironment to make it more conducive to CTL killing may be key in developing a successful anti-cancer immunotherapy.

Morse MA, Nair SK, Boczkowski D, Tyler D, Hurwitz HI, Proia A, Clay TM, Schlom J, Gilboa E, Lyerly HK.The feasibility and safety of immunotherapy with dendritic cells loaded with CEA mRNA following neoadjuvant chemoradiotherapy and resection of pancreatic cancer. Int J Gastrointest Cancer. 2002;32(1):1-6. Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.

BACKGROUND: Resected pancreatic cancer has a high risk of recurrence and mortality despite the the use of chemoradiotherapy. Because pancreatic cancers express tumor antigens such as carcinoembryonic antigen (CEA), it may be possible to immunize patients to induce tumor antigen-specific immune responses. We hypothesize that high-frequency tumor antigen-specific immune responses will reduce recurrence and increase survival. Autologous dendritic cells (DCs) loaded with tumor antigens are particularly potent at inducing tumor antigen-specific immune responses. METHODS: Three patients with resected pancreatic adenocarcinoma following neoadjuvant chemoradiotherapy received autologous, monocyte-derived DCs loaded with the mRNA encoding CEA monthly for 6 mo. RESULTS: It was feasible to generate an adequate number of DC from these patients and to cryopreserve them for repeated use. The DC demonstrated the typical immature phenotype. The immunizations were well-tolerated without evidence of adverse events. All three developed injection site reactivity. All three are alive without evidence of disease at more than 2 1/2 yr from the original diagnosis. CONCLUSION: The postoperative period following neoadjuvant chemoradiotherapy and pancreaticoduodenectomy for pancreatic cancer is an ideal environment to test novel immune-based therapies. DC-based immunotherapy in this setting is safe and feasible and may lead to prolonged survival.

Kaufman HL, Di Vito J Jr, Horig H. Immunotherapy for pancreatic cancer: current concepts.Kaufman HL, Di Vito J Jr, Horig H. Immunotherapy for pancreatic cancer: Hematol Oncol Clin North Am. 2002 Feb;16(1):159-97, viii. Department of Surgery, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA. kaufman@aecom.yu.edu

Despite advances in chemotherapy and surgical technique, patients with pancreatic cancer often succumb to local recurrence or metastatic spread. The need for new therapeutic strategies for this disease coupled with a better understanding of basic immunology have led to the development of novel anti-tumor vaccines. This review focuses on the historical development of tumor vaccines emphasizing the identification of potential pancreatic tumor antigens. The role of both B-cell and T-cell responses in tumor rejection will be reviewed. Methods for antigen presentation, including peptides, recombinant viral and bacterial vectors, dendritic cells, and whole cell approaches will be discussed. The use of immune adjuvants and improved methods of vaccine delivery will also be explored. The full potential for the immunotherapy of pancreatic cancer awaits the results of early phase clinical trials. The development of pancreatic cancer vaccines represents a useful paradigm for the translation of basic research into the clinical arena.

Schnurr M, Scholz C, Rothenfusser S, Galambos P, Dauer M, Robe J, Endres S, Eigler A. Apoptotic pancreatic tumor cells are superior to cell lysates in promoting cross-priming of cytotoxic T cells and activate NK and gammadelta T cells. Cancer Res. 2002 Apr 15;62(8):2347-52.

Department of Medicine, Divisions of Clinical Pharmacology and Gastroenterology, Ludwig-Maximilians-University of Munich, 80336 Munich, Germany.

Tumor vaccines using dendritic cells (DCs) have been shown to induce antitumor CTL responses. The choice of the tumor antigen preparation used for DC loading is still an unresolved issue. We compared DCs pulsed with cell lysates, whole apoptotic tumor cells or their supernatants of the HLA-A2(+) human pancreatic carcinoma cell line Panc-1 for their capacity to activate T cells. Monocyte-derived DCs from HLA-A2(+) donors were pulsed with tumor antigen, matured subsequently, and cocultured with autologeous peripheral blood mononuclear cells. After three weekly restimulations with DCs, T-cell activation was assessed by intracellular IFN-gamma staining and cytotoxicity assays. Compared with lysate, pulsing DCs with the supernatant of apoptotic tumor cells induced a higher frequency of activated CTLs and T-helper cells, as well as an enhanced MHC class I-restricted tumor cell lysis. No activation of natural killer (NK) or gammadelta T cells was detected. Pulsing DCs with whole apoptotic tumor cells induced an even more pronounced lytic effect. However, in this case, MHC class-I blocking was only partially effective, and unrelated cell lines were also killed. IFN-gamma staining revealed activation of CTLs and T-helper cells, as well as NK and gammadelta T cells. Trans-well cultures of NK cells, apoptotic tumor cells, and DCs showed that NK cell activation was dependent on direct cell-to-cell contact with tumor cells and the presence of interleukin-12 produced by DCs. These results indicate that the choice of antigen preparation is a critical determinant in the induction of antitumor immunity. Tumor vaccines consisting of DCs and apoptotic tumor cells may be able to activate CTLs, as well as effector cells of the innate immune system.

Immunologic approaches to the management of pancreatic cancer. Laheru D, Biedrzycki B, Jaffee EM. Immunologic approaches to the management of pancreatic cancer. Laheru D, Cancer J. 2001 Jul-Aug;7(4):324-37. Department of Medical Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231-1000, USA.

Pancreatic cancer remains one of the most difficult cancers to treat; very few effective therapies are available, with surgery being the sole chance for cure-yet surgery is not a viable option for most pancreatic cancer patients. Immunotherapy has the potential to provide a non-cross-resistant mechanism of antitumor activity that can be integrated with surgery, radiation therapy, and chemotherapy. However, the inherent instability of the tumorgenome as well as tumor tolerance mechanisms are significant practical obstacles that must be overcome if immune-based approaches for pancreatic cancer can achieve its promise. Recent advances in both tumor immunology and vaccine design have already resulted in promising preliminary data from phase I studies, and additional trials are already in progress. This article summarizes some of the progress and challenges in immunotherapy research.

Schnurr M, Galambos P, Scholz C, Then F, Dauer M, Endres S, Eigler A.Tumor cell lysate-pulsed human dendritic cells induce a T-cell response against pancreatic carcinoma cells: an in vitro model for the assessment of tumor vaccines. Cancer Res. 2001 Sep 1;61(17):6445-50. Division of Clinical Pharmacology, Department of Medicine, Ludwig-Maximilians-University of Munich, 80336 Munich, Germany.

Dendritic cells (DCs) are potent antigen-presenting cells and play a pivotal role in T cell-mediated immunity. DCs have been shown to induce strong antitumor immune responses in vitro and in vivo, and their efficacy is being investigated in clinical trials. Compared with vaccination strategies directed against a single tumor antigen, tumor-cell lysate as the source of antigen offers the potential advantage of inducing a broad T-cell response against multiple known, as well as unknown, tumor-associated antigens expressed by the individual tumor. We used pancreatic carcinoma cell lines to develop an in vitro model for monitoring T-cell responses induced by lysate-pulsed DCs. Monocyte-derived DCs of HLA-A2(+) donors were pulsed with lysate generated from the HLA-A2(+) pancreatic carcinoma cell line Panc-1. In some experiments, the immunogenic protein keyhole limpet hemocyanin (KLH) was added to the lysate. Subsequently, the antigen-loaded DCs were activated with tumor necrosis factor-alpha and prostaglandin E(2). Autologous mononuclear cells were cocultured with DCs in the presence of low-dose interleukin (IL)-2 and IL-7 and were restimulated weekly with new DCs. High levels of IL-12 and IFN-gamma could be detected in the supernatants, indicating a T-helper type 1-type immune response. This cytokine profile was associated with the expression of the activation marker CD69 on both T helper and CTLs and with an antigen-induced proliferative T-cell response. After 4 weeks, CTL-mediated cytotoxicity was assessed. Tumor cell lysis was specific for Panc-1 tumor cells and was MHC class I-restricted. Cytokine secretion, CD69 expression of T cells, and antigen-induced T-cell proliferation correlated with the cytotoxic activity and were more pronounced when KLH was added to the lysate. This is the first study to show that T cells specific for pancreatic carcinoma cells can be generated in vitro by lysate-pulsed DCs and that the T-cell response can be enhanced by KLH. This in vitro model can be applied to compare different strategies in the development of DC-based tumor vaccines.

Schott M, Feldkamp J, Lettmann M, Simon D, Scherbaum WA, Seissler J.Dendritic cell immunotherapy in a neuroendocrine pancreas carcinoma. Clin Endocrinol (Oxf). 2001 Aug;55(2):271-7. Department of Endocrinology, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany. schottmt@uni-duesseldorf.de

OBJECTIVE: Metastatic neuroendocrine carcinomas of the pancreas frequently fail to respond to conventional therapies, including radiation and chemotherapy. We therefore tested a dendritic cell-based immunotherapy in an attempt to eradicate residual tumour masses in a patient suffering from a metastatic insulin-producing pancreatic carcinoma. DESIGN: Autologous dendritic cells (DCs) were generated from peripheral blood monocytes in the presence of granulocyte/macrophage colony-stimulating factor, interleukin-4 and tumour necrosis factor alpha. DCs were loaded with tumour-derived lysate (TL), and were delivered by subcutaneous injections in 4-week intervals. RESULTS: Three weeks after first treatment, the patient developed a strong delayed-type hypersensitivity (DTH) skin reaction with an erythema and induration after the challenge with TL-pulsed DCs, which indicates the efficient generation of antigen-specific memory T-cells. Immunohistochemical analysis of skin biopsy demonstrated a strong perivascular and epidermal infiltration by T-helper (CD4 positive) and cytotoxic T cells (CD8 positive). Stimulation with TL revealed a dose-dependent T-cell proliferation with a stimulation index of 1.1-5.7 compared to 1.1-1.4 before vaccination (P < 0.01). Most strikingly, DC-based vaccination was accompanied by a steady decrease of the tumour marker chromogranin A from 2.93 umol/l initially to below the detection limit of 0.15 umol/l within 9 months of therapy. The ultrasound examination revealed a tumour regression of the metastasis in the right lobe of the liver. CONCLUSIONS: Our data indicate that vaccination with tumour lysate-pulsed DCs induced a significant antitumour immune response in a neuroendocrine carcinoma of the pancreas. This approach represents an alternative strategy for the treatment of advanced neuroendocrine carcinomas that are resistant to conventional therapy.