GM-CSF as therapy

[Rich66]

(monotherapy success in pretreated, immuno, antiangiogenic w/thalidomide or revlimid, w/cyclo, w/Letrozole, support role, increases bone mets?)


Oncology (Williston Park). 2005 Apr;19(4 Suppl 2):23-6.
Continuous low-dose GM-CSF as salvage therapy in refractory recurrent breast or female genital tract carcinoma.

Click for Full Text

Kurbacher CM, Kurbacher JA, Cramer EM, Rhiem K, Mallman PK, Reichelt R, Reinhold U, Stier U, Cree IA.
Institute of Gynecologic Oncology, Bonn Comprehensive Cancer Network, Germany. praxis.kurbacher@online.ms
Granulocyte-macrophage colony-stimulating factor (GM-CSF, sargramostim [Leukine]) is a powerful cytokine that is able to stimulate the generation of dendritic cells. Adjuvant treatment with continuous low-dose GM-CSF has been shown to prolong survival of stage III/IV melanoma patients. Data on continuous low-dose GM-CSF therapy in tumors other than prostate cancer are still lacking. This pilot trial was initiated in order to evaluate the efficacy and tolerability of continuous low-dose GM-CSF as salvage in various chemotherapy-refractory carcinomas. A total of 19 patients who had failed a median of 4 prior chemotherapies were included. Their malignancies included metastatic breast cancer, recurrent ovarian carcinoma, metastatic endometrial carcinoma, and recurrent squamous cell cancer of the cervix uteri. Continuous low-dose GM-CSF was delivered subcutaneously at a daily starting dose of 125 microg. GM-CSF was increased at 25-microg increments until a maximum of 250 microg was reached or when mild leukocytosis (10-20 g/L) was achieved, providing that the relative eosinophil count did not exceed 15%. Therapy was continued until progression or refusal by the patient. Toxicity was generally mild. Only one patient was withdrawn due to grade 3 fatigue. In three additional patients, temporary dose reduction was necessary because of grade 1 injection site reactions, which recovered spontaneously. Mild to moderate leukocytosis was obvious in 10 patients. Systemic hypersensitivity-like reactions did not occur and no patient required hospitalization for other life-threatening side effects. The objective response rate was 37%: 1 complete and 6 partial responses, 4 disease stabilizations, 8 progression of disease. Median response duration was 6 months. Notably, 6 of 7 responders but only 1 of 8 patients with disease progression developed leukocytosis during therapy. Therefore, we conclude that continuous low-dose GM-CSF has substantial activity in heavily pretreated patients with either metastatic breast cancer or female genital tract cancer. Achievement of mild leukocytosis seems to be a predictor of response.

PMID: 15934497 [PubMed - indexed for MEDLINE]



Oncology (Williston Park). 2005 Apr;19(4 Suppl 2):19-22.
Docetaxel and vinorelbine plus GM-CSF in malignant melanoma. (DVS regimen)

Fruehauf JP, Kong KM, Jakowatz JG.
University of California Irvine, Chao Family Comprehensive Cancer Center, Orange, California 92868, USA. johnfruehauf@msn.com
Patients having locoregional or metastatic melanoma have a poor prognosis, with 50% to 100% of patients dying from the disease within 5 years. Current chemotherapy regimens offer limited benefits to these patients, and more effective and less toxic treatments are needed. We therefore piloted a study of docetaxel (Taxotere), vinorelbine (Navelbine), granulocyte-macrophage colony-stimulating factor (GM-CSF, sargramostim [Leukine]), or the DVS regimen, in patients with stage IV melanoma. Eight patients were treated after previous biochemotherapy and two patients were given the regimen as an initial treatment. The DVS regimen consisted of docetaxel at 40 mg/m2 i.v. over 1 hour, vinorelbine at 30 mg/m2 i.v. over 6 to 10 minutes every 14 days, and GM-CSF at 250 mg/m2 SC on days 2 to 12. No grade 3 or 4 toxicities were encountered. Of the 10 patients evaluable for response, 5 were partial responders (50% response rate). Time to progression for the 10 cases ranged from 2 to 26+ months (median: 8 months). The DVS regimen was active against advanced melanoma in both previously treated and untreated patients. A larger study to confirm the activity of the DVS regimen for stage IV melanoma is currently under way.

PMID: 15934496 [PubMed - indexed for MEDLINE]




J Urol. 2006 Jun;175(6):2087-91.
Clinical and immunological characteristics of patients with serologic progression of prostate cancer achieving long-term disease control with granulocyte-macrophage colony-stimulating factor.

Rini BI, Fong L, Weinberg V, Kavanaugh B, Small EJ.
University of California-San Francisco Comprehensive Cancer Center, San Francisco, California, USA. rinib2@ccf.org
Comment in:

• J Urol. 2007 Apr;177(4):1585; author reply 1585-6.

PURPOSE: We describe the clinical and immunological characteristics of patients with biochemically relapsed prostate cancer who achieved long-term disease control with GM-CSF (Leukine). MATERIALS AND METHODS: A total of 30 patients with prostate cancer and nonmetastatic recurrent disease, as manifested by increasing PSA between 0.4 and 6.0 ng/ml after prior definitive therapy, were enrolled in a phase II trial. Patients received 250 microg/m2 GM-CSF daily subcutaneously on days 1 through 14 of a 28-day cycle until PSA or objective progression. The patient and disease characteristics of patients who remained without evidence of disease progression beyond 4 years were examined. Additionally, flow cytometry was performed in peripheral blood to characterize monocyte and dendritic cells. RESULTS: Seven of 29 evaluable patients (24%) remained free of disease progression at a median of 5.1 years (range 4.5 to 5.6 or greater) from the start of GM-CSF therapy. Patients on long-term GM-CSF tended to have lower initial T stage, Gleason score and pretreatment PSA. An increase in the number of circulating monocytes and dendritic cells was observed after 14 days of GM-CSF treatment. These values returned to baseline during the 14-day off period. CONCLUSIONS: GM-CSF modulates PSA in androgen dependent, biochemically relapsed cases. A substantial proportion of patients achieve long-term disease control. The clinical characteristics described may help select patients for future clinical trials with GM-CSF or other immunomodulators. Additional investigation is required to define the immunological mechanism of GM-CSF in prostate cancer.

PMID: 16697809 [PubMed - indexed for MEDLINE]




Clin Cancer Res. 1999 Jul;5(7):1738-44.
Therapy of advanced prostate cancer with granulocyte macrophage colony-stimulating factor.

Small EJ, Reese DM, Um B, Whisenant S, Dixon SC, Figg WD.
Department of Medicine, University of California, San Francisco 94115, USA. eric_small@quickmail.ucsf.edu
Granulocyte macrophage colony-stimulating factor is a pleiotropic cytokine capable of inducing systemic immune responses against experimental and human tumors. To evaluate the efficacy of GM-CSF treatment in patients with hormone-refractory prostate cancer, we conducted sequential Phase II studies in 36 men with progressive disease after androgen deprivation and antiandrogen withdrawal. In a first cohort of patients (n = 23), GM-CSF was administered s.c. at a dose of 250 microg/m2 daily for 14 days of a 28-day treatment period. After we observed oscillating prostate-specific antigen (PSA) responses in several patients in this first cohort, a second trial was performed in which patients (n = 13) received maintenance GM-CSF (250 microg/m2 three times weekly) after the first 14 days of daily GM-CSF. All patients were treated until disease progression. Response was assessed by evaluation of serial changes in serum PSA and sequential imaging studies. In cohort I, 10 of 22 patients (45%) had a PSA versus time plot with a sawtooth pattern, with PSA declining during GM-CSF therapy and climbing during the off-therapy period; 5 patients had at least two consecutive declines in PSA, with a median response duration of 3.5 months. All but one patient in cohort II experienced a decline in PSA (median decline, 32%), but a PSA decline greater than 50% and sustained for more than 6 weeks was seen in only one patient, who had a >99% decline in PSA and an improvement in bone scan lasting for 14+ months. Changes in PSA levels could not be attributed to direct or indirect effects of GM-CSF on the PSA assay or down-regulation of PSA expression by GM-CSF. Toxicity was very mild, consisting primarily of transient constitutional symptoms and injection site reactions. These data suggest that GM-CSF may have antitumor activity in advanced prostate cancer, and the use of GM-CSF may be a confounding variable when PSA responses are used as an end point in clinical trials evaluating new regimens for the treatment of advanced prostate cancer.

PMID: 10430077 [PubMed - indexed for MEDLINE]



PCAAC: Prostate cancer antiangiogenic cocktail (2002, Liebowitz):

http://compassionateoncology.org/pdfs/cocktail9602.pdf

Quote:

The use of multi-target therapeutic strategies, in particular inhibitors of angiogenesis with metronomic schedules of cytotoxic agents, is to achieve long-term control of cancer, or induce a dormant state in residual areas of tumor, without unacceptable toxic effects. It appears that survival time depends more on merely containing cancer than on actually shrinking it. The goal of chemotherapy has always been to shrink cancer. We must realistically appreciate that we are not going to be able to cure metastatic prostate cancer. We can, however, achieve very long-term control.

Quote:

patients are being treated with GM-CSF, interferon, Proscar, Celebrex, Herceptin, thalidomide, low-dose Cytoxan and Lovenox (or Coumadin).

2008 Liebowitz AAC update: http://compassionateoncology.org/pdf...tail082508.pdf

Quote:

Over the years, various ingredients in my AAC would appear, but if I was not impressed with their ability to help control prostate cancer (CaP), their inclusion in the AAC was shortlived. However, a few medications have enjoyed charter member status. The two most effective drugs are clearly Leukine (GM-CSF) and the combination of thalidomide/Revlimid. For most patients, insurance coverage permitting, we use thalidomide 50 mg, alternating with Revlimid 5 mg. We never use both drugs the same day, nor do we ever use more than one total capsule on
any day.

Quote:

Unlike thalidomide, Revlimid does not cause drowsiness, peripheral neuropathy symptoms, constipation, or slow heart rates. Revlimid may lower a patient’s platelet count. Platelets help your blood to clot. We monitor blood counts carefully and frequently whenever one of our patients is being treated with Revlimid.
As of August 2008, I believe (opinion) that 95% of the beneficial results from AAC are due to Leukine and thalidomide/Revlimid.
Some of the minor AAC players that may help our patients include Proscar, Avodart, Celebrex (but only 200 mg once a day to reduce the risk of cardiovascular
complications), and statins (like Crestor) to lower cholesterol and reduce the risk of dying from cardiovascular events. A number of studies have found that men on statins who develop prostate cancer have a lower risk of developing advanced or
metastatic cancer, as well as a lower risk of dying from metastatic prostate cancer. Still other minor AAC players include anticoagulation with low-molecular weight heparin (not warfarin/Coumadin), mini-mini-dose alpha interferon, and perhaps vitamin D. Avastin is also possibly a major significant player and we try to use it in certain settings, but I do not believe it is anywhere near as effective as Leukine and thalidomide/Revlimid. We also may use a metronomic schedule of oral cyclophosphamide (Cytoxan) in tiny mini-doses. At times, we may add another category of drugs called targeted therapy. Currently, our targeted drug of choice is Nexavar, but previously we tried Iressa, Tarceva, Sutent, and Gleevec.

Quote:
One of the nicest things about this regimen is that both of these medications enhance the immune system. Many cancer patients are concerned that chemotherapy can adversely affect their immune system; with Leukine and thalidomide, the opposite occurs.




Gynecol Oncol. 2009 Nov 17. [Epub ahead of print]
Phase II trial of GM-CSF in women with asymptomatic recurrent müllerian tumors.

Roche MR, Rudd PJ, Krasner CN, Matulonis UA, Berlin ST, Lee H, Silver M, Tran CD, Seiden MV, Penson RT.
Dana-Farber/Harvard Cancer Center, representing members of the DF/HCC Gynecologic Oncology Research Group at Massachusetts General Hospital, and Dana-Farber Cancer Institute, Boston, MA, USA.
OBJECTIVE.: GM-CSF is a recombinant human cytokine, which promotes the proliferation and differentiation of granulocytes and monocytes, and is associated with anti-tumor activity. The primary objective was to define the median time to treatment termination (TTT) with women with relapsed ovarian cancer treated with single agent GM-CSF delivered subcutaneously (SC). PATIENTS AND METHODS.: Open label phase II study in asymptomatic patients with recurrent müllerian malignancy without an indication for immediate systemic chemotherapy. In the first cohort of 35 women, GM-CSF 250 mug/m(2) was administered SC on days 1-14 of a 28-day cycle, the second cohort received continuous GM-CSF 150 mug/m(2) given with dose escalation. RESULTS.: Seventy-two women were enrolled. Best overall response included one complete response, and 20 patients with stable disease (23%), 4 of whom had stable disease for >6 months. Median TTT was 78 days. Toxicity in both cohorts was generally mild; however, four patients experienced excessive toxicity and withdrew consent. In the first cohort, CA-125 dropped in 70% of women from their baseline on study value (median change -23%, range -48 to +116%) after 14 days of GM-CSF. The magnitude of CA-125 drop during the first 2 weeks of therapy also showed a positive inverse correlation with day 15 white cell count for the whole group (p=0.038). CONCLUSION.: GM-CSF is well tolerated and frequently associated with a decline in CA-125 that is correlated with leukocytosis. Although median TTT is modest, a subset of women had prolonged stable disease.

PMID: 19922985 [PubMed - as supplied by publisher]


J Clin Oncol. 2009 Nov 16. [Epub ahead of print]
Phase II Multicenter Trial of Maintenance Biotherapy After Induction Concurrent Biochemotherapy for Patients With Metastatic Melanoma.

O'Day SJ, Atkins MB, Boasberg P, Wang HJ, Thompson JA, Anderson CM, Gonzalez R, Lutzky J, Amatruda T, Hersh EM, Weber JS.
The Angeles Clinic and Research Institute; John Wayne Cancer Institute, Santa Monica; University of Southern California, Los Angeles, CA; Harvard/Beth-Israel Medical Center, Boston, MA; University of Washington, Seattle, WA; University of Missouri, Columbia, MO; University of Colorado, Denver, CO; Mount Sinai Hospital, Miami, FL; The Humphrey Cancer Center, Robbinsdale, MN; and University of Arizona, Tuscon, AZ.
PURPOSE: Biochemotherapy improves responses in metastatic melanoma, but not overall survival, in randomized trials. We developed a maintenance biotherapy regimen after induction biochemotherapy in an attempt to improve durability of responses and overall survival. PATIENTS AND METHODS: One hundred thirty-three chemotherapy-naïve patients with metastatic melanoma without CNS metastases were treated at 10 melanoma centers. The biochemotherapy induction regimen included cisplatin, vinblastine, dacarbazine, decrescendo interleukin-2 (IL-2), and interferon alfa-2b with granulocyte-macrophage colony-stimulating factor (GM-CSF) cytokine support. Patients not experiencing disease progression were eligible for maintenance biotherapy with low-dose IL-2 and GM-CSF followed by intermittent pulses of decrescendo IL-2 over 12 months. Patients were observed for response, progression-free survival, toxicity, and overall survival. RESULTS: The response rate to induction biochemotherapy was 44% (95% CI, 35% to 52%; complete response, 8%; partial response, 36%; stable disease, 29%). The median number of biochemotherapy cycles was four, and the median number of maintenance biotherapy cycles was five. The median progression-free survival was 9 months, and the median survival was 13.5 months. The 12-month and 24-month survival rates were 57% and 23%, respectively. Twenty percent of patients remain alive (12 without disease), with median follow-up of 30 months (95% CI, 25+ to 45+ months). Thirty-nine percent of patients developed CNS metastases. The median times to CNS progression and death were 8 months and 5 months, respectively. CONCLUSION: Maintenance biotherapy after induction biochemotherapy seems to prolong progression-free survival and improve overall survival compared with recent multicenter trials of biochemotherapy or chemotherapy. The regimen should be studied in a randomized clinical trial in patients with advanced metastatic melanoma. CNS progression remains a formidable challenge.

PMID: 19917850 [PubMed - as supplied by publisher]



J Clin Oncol. 2008 Nov 20;26(33):5436-42. Epub 2008 Oct 6.
Immunoembolization of malignant liver tumors, including uveal melanoma, using granulocyte-macrophage colony-stimulating factor.

Sato T, Eschelman DJ, Gonsalves CF, Terai M, Chervoneva I, McCue PA, Shields JA, Shields CL, Yamamoto A, Berd D, Mastrangelo MJ, Sullivan KL.
Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA 19107, USA. t_sato@mail.jci.tju.edu
PURPOSE: We conducted a phase I study to investigate the feasibility and safety of immunoembolization with granulocyte-macrophage colony-stimulating factor (GM-CSF; sargramostim) for malignant liver tumors, predominantly hepatic metastases from patients with primary uveal melanoma. PATIENTS AND METHODS: Thirty-nine patients with surgically unresectable malignant liver tumors, including 34 patients with primary uveal melanoma, were enrolled. Hepatic artery embolization accompanied an infusion of dose-escalated GM-CSF (25 to 2,000 microg) given every 4 weeks. Primary end points included dose-limiting toxicity and maximum tolerated dose (MTD). Patients who completed two cycles of treatments were monitored for hepatic antitumor response. Survival rates of patients were also monitored. RESULTS: MTD was not reached up to the dose level of 2,000 microg, and there were no treatment-related deaths. Thirty-one assessable patients with uveal melanoma demonstrated two complete responses, eight partial responses, and 10 occurrences of stable disease in their hepatic metastases. The median overall survival of intent-to-treat patients who had metastatic uveal melanoma was 14.4 months. Multivariate analyses indicated that female sex, high doses of GM-CSF (> or = 1,500 microg), and regression of hepatic metastases (complete and partial responses) were correlated to longer overall survival. Moreover, high doses of GM-CSF were associated with prolonged progression-free survival in extrahepatic sites. CONCLUSION: Immunoembolization with GM-CSF is safe and feasible in patients with hepatic metastasis from primary uveal melanoma. Encouraging preliminary efficacy and safety results warrant additional clinical study in metastatic uveal melanoma.

PMID: 18838710 [PubMed - indexed for MEDLINE]


Different drug but same problematic issue??:

Cancer Res. 2009 Oct 1;69(19):7524-8. Epub 2009 Sep 8.
Contribution of granulocyte colony-stimulating factor to the acute mobilization of endothelial precursor cells by vascular disrupting agents.

Shaked Y, Tang T, Woloszynek J, Daenen LG, Man S, Xu P, Cai SR, Arbeit JM, Voest EE, Chaplin DJ, Smythe J, Harris A, Nathan P, Judson I, Rustin G, Bertolini F, Link DC, Kerbel RS.
Department of Molecular Pharmacology, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel. yshaked@tx.technion.ac.il
Vascular disrupting agents (VDA) cause acute shutdown of abnormal established tumor vasculature, followed by massive intratumoral hypoxia and necrosis. However, a viable rim of tumor tissue invariably remains from which tumor regrowth rapidly resumes. We have recently shown that an acute systemic mobilization and homing of bone marrow-derived circulating endothelial precursor (CEP) cells could promote tumor regrowth following treatment with either a VDA or certain chemotherapy drugs. The molecular mediators of this systemic reactive host process are unknown. Here, we show that following treatment of mice with OXi-4503, a second-generation potent prodrug derivative of combretastatin-A4 phosphate, rapid increases in circulating plasma vascular endothelial growth factor, stromal derived factor-1 (SDF-1), and granulocyte colony-stimulating factor (G-CSF) levels are detected. With the aim of determining whether G-CSF is involved in VDA-induced CEP mobilization, mutant G-CSF-R(-/-) mice were treated with OXi-4503. We found that as opposed to wild-type controls, G-CSF-R(-/-) mice failed to mobilize CEPs or show induction of SDF-1 plasma levels. Furthermore, Lewis lung carcinomas grown in such mice treated with OXi-4503 showed greater levels of necrosis compared with tumors treated in wild-type mice. Evidence for rapid elevations in circulating plasma G-CSF, vascular endothelial growth factor, and SDF-1 were also observed in patients with VDA (combretastatin-A4 phosphate)-treated cancer. These results highlight the possible effect of drug-induced G-CSF on tumor regrowth following certain cytotoxic drug therapies, in this case using a VDA, and hence G-CSF as a possible therapeutic target.

PMID: 19738066 [PubMed - in process]



Expert Opin Investig Drugs. 2010 Jan 5. [Epub ahead of print]
Combining low-dose cyclophosphamide with GM-CSF-secreting prostate cancer immunotherapy enhances antitumor immune effects Evaluation of: Wada S, Yoshimura K, Hipkiss EL, et al. Cyclophosphamide augments antitumor immunity: studies in an autochthonous prostate cancer model. Cancer Res. 2009;69:4309-18.

Antonarakis ES, Carducci MA.
Johns Hopkins University, Sidney Kimmel Comprehensive Cancer Center, 1650 Orleans Street, CRB1-191, Baltimore, MD 21231, USA +1 410 614 4459 ; +1 410 955 0125 ; eantona1@jhmi.edu.
Prostate GVAX((R)) is an allogeneic cell-based prostate cancer vaccine engineered to secrete GM-CSF. The release of GM-CSF by this immunotherapy serves to recruit dendritic cells, which then present tumor antigens to T cells, thus initiating antitumor immune responses. However, preclinical data show that, when used alone, cell-based immunotherapy is generally unable to break specific T-cell tolerance in tumor-bearing hosts. The study by Wada and colleagues employed an autochthonous prostate cancer mouse model to demonstrate that low-dose cyclophosphamide given prior to a cell-based GM-CSF-secreting vaccine (T-GVAX) abrogated immune tolerance, augmented prostatic CD8(+) T-cell infiltration, mediated depletion of regulatory T cells (Tregs), and increased expression of dendritic cell maturation markers. In addition, this combination decreased the wet weight of mouse prostate glands, lowered histological tumor scores, and increased the density of apoptotic bodies. These findings add to existing data from other preclinical models showing enhancement of antitumor immunity when cyclophosphamide is administered in sequence with GM-CSF-secreting immunotherapy for the treatment of breast and pancreatic cancers. These studies provide a rationale for designing clinical trials that combine low-dose cyclophosphamide with GM-CSF-secreting cell-based immunotherapy in patients with prostate and other cancers.

PMID: 20047504 [PubMed - as supplied by publisher]


Clin Exp Metastasis. 2009;26(3):179-87. Epub 2008 Dec 14.
Chitosan hydrogel containing GMCSF and a cancer drug exerts synergistic anti-tumor effects via the induction of CD8+ T cell-mediated anti-tumor immunity.

Seo SH, Han HD, Noh KH, Kim TW, Son SW.
Department of Dermatology, Korea University Ansan Hospital, Korea University College of Medicine, Gojan 1-dong, Danwon-gu, Ansan-si, Gyeonggi-do, South Korea.
Cancer treatments consisting of a combination of chemotherapy and immunotherapy have been vigorously exploited to further improve the efficacy of cancer therapies. In this study, we utilized a chitosan hydrogel (CH) system loaded with GMCSF and a cancer drug as a chemo-immunotherapeutic agent in an effort to assess the effects on tumor growth in mice using TC-1 cervical tumor cells, which express the tumor-specific antigen, HPV-16 E7. The growth of TC-1 tumors was significantly reduced in mice treated with a CH harboring a cancer drug (doxorubicin (DOX), cisplatin (CDDP), or cyclophosphamide (CTX)) and GMCSF (CH-a cancer drug + GMCSF), as compared to other groups that were treated with CH containing only a cancer drug(CH-a cancer drug) or GMCSF(CH-GMCSF). Among the cancer drugs, CTX exerted the most potent anti-tumor effects. Interestingly, the intra-tumoral injection of CH-a cancer drug + GMCSF induced a significant E7-specific CD8(+) T cell immune response as compared to CH-GMCSF or CH-a cancer drug. This enhancement of tumor antigen-specific CD8(+) T cell immunity was associated principally with the anti-tumor effects induced by CH-CTX + GMCSF, as demonstrated by antibody depletion. Collectively, the aforementioned results indicate that co-treatment of tumors with a combination of GMCSF and a cancer drug incorporated into a CH system results in synergistic anti-tumor effects, which occur via the induction of a tumor antigen-specific CD8(+) T cell-mediated anti-tumor immunity. This study demonstrates the use of a biodegradable hydrogel system for the co-delivery of an immunoadjuvant and an anti-cancer drug for successful chemo-immunotherapy.

PMID: 19082918 [PubMed - indexed for MEDLINE]


Cancer Res. 2010 Jun 15;70(12):5014-23. Epub 2010 May 25.
Reversal of chemotherapy-induced leukopenia using granulocyte macrophage colony-stimulating factor promotes bone metastasis that can be blocked with osteoclast inhibitors.

Dai J, Lu Y, Yu C, Keller JM, Mizokami A, Zhang J, Keller ET.
Department of Urology, University of Michigan, Ann Arbor, Michigan 48109-8940, USA.



Abstract

Hematopoietic growth factors are used to reverse chemotherapy-induced leukopenia. However, some factors such as granulocyte macrophage colony-stimulating factor (GM-CSF) induce osteoclast-mediated bone resorption that can promote cancer growth in the bone. Accordingly, we evaluated the ability of GM-CSF to promote bone metastases of breast cancer or prostate cancer in a mouse model of chemotherapy-induced leukopenia. In this model, GM-CSF reversed cyclophosphamide-induced leukopenia but also promoted breast cancer and prostate cancer growth in the bone but not in soft tissue sites. Bone growth was associated with the induction of osteoclastogenesis, yet in the absence of tumor GM-CSF, it did not affect osteoclastogenesis. Two osteoclast inhibitors, the bisphosphonate zoledronic acid and the RANKL inhibitor osteoprotegerin, each blocked GM-CSF-induced tumor growth in the bone but did not reverse the ability of GM-CSF to reverse chemotherapy-induced leukopenia. Our findings indicate that it is possible to dissociate the bone-resorptive effects of GM-CSF, to reduce metastatic risk, from the benefits of this growth factor in reversing leukopenia caused by treatment with chemotherapy.

PMID: 20501834 [PubMed - in process]PMCID: PMC2888854 [Available on 2011/6/1]

[Becky]

Nice finds as the first two studies I have not seen. I used GM-CSF (brand name Leukine) instead of Neulasta as my white cell booster taking it days 2-12 after every chemo cycle and for 2-9 after my last chemo cycle.

Who knows why I continue to do well? I pulled out all the stops at the time because Herceptin was not available in the adjuvant setting at the time (even though I got it starting 4 months after chemo was completed).
Leukine was hard to take but I have no reference point on using it versus Neulasta. My first 10 injections after my first chemo instilled profound fatigue and vertigo - especially after the first injection.

GM-CSF is used in all the vaccine trials due to its ability to boost all components of the white blood cell types, not just the neutrophils as Neulasta and Neupogen do. It produces a 9X count on the dendrites, critical to self immunization to cancer cells. I used to always tell myself that I could do this as I was potentially creating a self immunizing (vaccine) system within myself.

Thanks for this post Rich and all the others you post as well.

PS - I did experience leukocytosis with a normal neutrophil count but greatly increased monocytes and lymphocytes. My basophils and einocyphils were increased which exasperated allergic responses (had some trouble with this but could not take antihistimines which would counteract the leukocytosis (which you want to have happen)). Another thing you want to have happen while on this therapy is hives at the injection site and I got that too. A real pain of a side effect but apparently, unless you don't start to get them after shot 7, it may not be doing the job. I was excited when I got the hives (sick, eh?) and then I had to put up with the 4 months of that which is a pain in the butt. You can see I have the Leukine in my signature.

[Rich66]

"I had to put up with the 4 months of that which is a pain in the butt."
Amazing. Butt pain is a good sign too?
Thanks for the details. I didn't realize it was different from Neupogen. Do you think this is a better way to recover wbc? (I have heard concern over wbc creating stem cells being activated too close to chemo, which then kills them.) I was actually thinking, if there wasn't a downside, that it would be a perfect compliment to longer interval chemos and breaks between chemos. Sounds like you had it pretty close to your Taxol. Did your onc come up with this approach?

[Becky]

I did tons of research prior to therapy. My onc was going to do Neulasta but said he would do Leukine without hesitation. I used Leukine after all cycles, including my 4 AC treatments and the Taxol treatments. Normally, Neulasta is not given after the last chemo (since you have all the time in the world to recover). But I got 7 daily injections of Leukine to re-boost the good stuff as my onc said that is why it is done.

It takes Leukine alittle longer to work than Neulasta/Neupogen to boost the neutrophils. My onc warned me that I may have to wait a couple of extra days and my dense dose therapy might be 2 weeks plus a couple of extra days (instead of just 2 weeks which was normal in my particular protocol) but that didn't happen to me. At the 2 week mark I was always ready to go. For my second treatment my onc told me my neutrophils were alittle low for treatment but my monocytes and lymphocytes were so high, he was going to go ahead with the treatment anyway. That was about the norm for me. The lymphocyte count being high is a great Leukine sign that perhaps you truly are self vaccinating and mine were astronomical (lymphocytes fight chronic infection or an infection you have regained (like if you already had the measles then get exposed again).

Any questions you have, just ask.

[Rich66]

Becky says "a total of 77 shots of Leukine @500 mcg each."

[Rich66]

• Our Experts

Leisha Emens, M.D., Ph.D.

Phone: (410) 955-8964

Fax: (410) 614-8216

Titles
Associate Professor of Oncology
Schools/Degrees
M.D., Medicine, Baylor College of Medicine, Houston, TX
Ph.D., Cell Biology, Baylor College of Medicine, Houston, TX
Training
Clinical Fellow in Hematology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD

Senior Clinical and Research Fellow in Medical Oncology, Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD

Susan B. Komen Clinical Breast Cancer Fellowship, Johns Hopkins Oncology Center

Intern and Resident, Internal Medicine, University of Texas Southwestern Affiliated Hospitals, Parkland Memorial Hospital and Dallas VA Medical Center, Dallas, TX

Postdoctoral Research Fellow, Laboratory of Biological Chemistry, National Cancer Instutitute, National Institutes of Health, Bethesda, MD

Predoctoral Fellow, Baylor College of Medicine, Houston, TX
Certifications
Internal Medicine
Medical Oncology
Hematology

Clinical Interests
Medical Oncology
Breast Cancer
Immunotherapy

PhysicianLeisha Emens and her patients are featured in the Baltimore Sun regarding a clinical trial on a breast cancer vaccine

Research Summary
Dr. Emens develops and tests active vaccination strategies for breast cancer treatment that are optimally integrated with traditional anticancer therapies and newer biologically targeted therapies in additive or synergistic ways. She developed a genetically-modified, cell-based vaccine for breast cancer that secretes the immune-stimulating hormone granulocyte-macrophage colony-stimulating factor (GM-CSF), and is testing the vaccine in combination with low doses of Cyclophosphamide (CY) and Doxorubicin (DOX) in patients with Stage 4 breast cancer. In a mouse model of spontaneous breast cancer where the vaccine does not work, adding CY and DOX cures about 30% of tumor-bearing mice. This chemotherapy effect is largely due to the ability of CY to turn off a special type of immune cell (regulatory T cell) that keeps immune responses shut down. Analysis of patient samples on this trial will yield insight into relevant immunoregulatory pathways in humans that will support the better design of future vaccine trials. Dr. Emens has also investigated the addition of monoclonal antibodies that target either the tumor itself (HER-2/neu), or the tumor microenvironment (vascular endothelial growth factor receptor 2 (VEGFR2) to chemotherapy-modulated vaccination. Both add futher to the antitumor effect of the vaccine. In particular, HER-2/neu-specific monoclonal antibodies augment antigen processing and presentation, resulted in higher numbers of CD8+ T cells after chemotherapy-modulated vaccination in the presence of the antibody. Based on these data, Dr. Emens is preparing to launch a clinical trial testing the HER-2/neu-specific monoclonal antibody in combination with CY-modulated vaccination in patients with HER-2/neu-overexpressing breast cancer. The overall goal of Dr. Emens research is to elucidate mechanisms of immunoregulation in patients with breast cancer using the vaccine in combination with standard breast cancer drugs and novel therapeutics. These studies should identify novel drug targets to improve breast cancer therapy.

Journal Citations
Davis-Sproul, J. M., Harris, M. P., Davidson, N. E., Kobrin, B. J., Jaffee, E. M. & Emens, L. A. (2005). Cost-effective manufacture of an allogeneic GM-CSF-secreting breast tumor vaccine in an academic cGMP facility. Cytotherapy 7, 46-56.

Emens, L. (2008). Jump-Starting Tumor Immunity with Breast Cancer Therapeutics. In: Cancer Vaccines and Tumor Immunity, ed. J.W.H.B.D. Rimas Orentas: Johnson, John Wiley and Sons, Inc.

Emens, L. A. & Jaffee, E. M. (2005). Leveraging the activity of tumor vaccines with cytotoxic chemotherapy. Cancer Res 65, 8059-64.

Emens, L. A. (2006). Editorial. Int Rev Immunol 25, 259-68.

Emens, L. A. (2006). Roadmap to a better therapeutic tumor vaccine. Int Rev Immunol 25, 415-43.

Emens, L. A. 2008. Chemotherapy and tumor immunity: an unexpected collaboration. Front Biosci 13:249-57.

Emens, L. A., Reilly, R. T. & Jaffee, E. M. (2005). Cancer vaccines in combination with multimodality therapy. Cancer Treat Res 123, 227-45.

Emens, L., Miller, KD, and Mehta, R. (2008). Physician Roles in Academia: The Physician–Scientist, Clinical Investigator, and Clinician-Educator. . In: Career Resources Guide for the American Society of Clinical Oncology., ed. L. Hutchins, Blayney, DW, Ochs, JS, and Schwartz, JE: ASCO, 150-164.

Emens, L.A. (2008). Cancer vaccines: on the threshold of success. Expert Opin Emerg Drugs 13, 295-308.

Kim, P.S., Armstrong, T.D., Song, H., Wolpoe, M.E., Weiss, V., Manning, E.A., Huang, L.Q., Murata, S., Sgouros, G., Emens, L.A., Reilly, R.T., and Jaffee, E.M. (2008). Antibody association with HER-2/neu-targeted vaccine enhances CD8 T cell responses in mice through Fc-mediated activation of DCs. J Clin Invest 118, 1700-1711.

Manning, E. A., J. G. Ullman, J. M. Leatherman, J. M. Asquith, T. R. Hansen, T. D. Armstrong, D. J. Hicklin, E. M. Jaffee, and L. A. Emens. 2007. A vascular endothelial growth factor receptor-2 inhibitor enhances antitumor immunity through an immune-based mechanism. Clin Cancer Res 13:3951-9.

Murata, S., Ladle, B. H., Kim, P. S., Lutz, E. R., Wolpoe, M. E., Ivie, S. E., Smith, H. M., Armstrong, T. D., Emens, L. A., Jaffee, E. M. & Reilly, R. T. (2006). OX40 costimulation synergizes with GM-CSF whole-cell vaccination to overcome established CD8+ T cell tolerance to an endogenous tumor antigen. J Immunol 176, 974-83.

Zellars, R.C., Stearns, V., Frassica, D., Asrari, F., Tsangaris, T., Myers, L., DiPasquale, S., Lange, J., Jacobs, L., Emens, L.A., Armstrong, D., Fetting, J., Garrett-Mayer, E., Davidson, N.E. and Wolff, A.C. (2009). Feasibility Trial of Partial Breast Irradiation with Concurrent Dose-Dense Doxorubicin and Cyclophosphamide in Early Stage Breast Cancer. J Clin Onc 27, 2816-2822.

Davis-Sproul, J., Harris, M. P., Davidson, N. E., Kobrin, B. J., Jaffee, E. M., & Emens, L. A. 2005. Cost-effective manufacture of an allogeneic GM-CSF-secreting breast tumor vaccine in an academic cGMP facility. Cytotherapy. 7:46-56.
Emens, L. A. 2005. Towards a breast cancer vaccine: the next steps. Expert Rev. Vaccines. 4:831-841.

Emens, L. A., & Jaffee, E. M. 2005. Leveraging the activity of tumor vaccines with cytotoxic chemotherapy. Cancer Res. 65:8059-8064.

Ercolini, A. M., Ladle, B. H., Manning, E. A., Pfannenstiel, L. W., Armstrong, T. D., Machiels, J. P., et al. 2005. Recruitment of latent pools of high avidity CD8(+) T cells to the antitumor immune response. J. Exp. Med. 201:1591-1602.



Clin Cancer Res. 2009 Nov 15;15(22):7036-44. Epub 2009 Nov 10.
Effect of granulocyte/macrophage colony-stimulating factor on circulating CD8+ and CD4+ T-cell responses to a multipeptide melanoma vaccine: outcome of a multicenter randomized trial.

Slingluff CL Jr, Petroni GR, Olson WC, Smolkin ME, Ross MI, Haas NB, Grosh WW, Boisvert ME, Kirkwood JM, Chianese-Bullock KA.
Department of Surgery/Division of Surgical Oncology, Department of Public Health Sciences, and Department of Medicine/Division of Hematology-Oncology, University of Virginia, Charlottesville, Virginia, USA.
PURPOSE: Granulocyte/macrophage colony-stimulating factor (GM-CSF) administered locally together with vaccines can augment T-cell responses in animal models. Human experience has been limited to small and uncontrolled trials. Thus, a multicenter randomized phase II trial was done to determine whether local administration of GM-CSF augments immunogenicity of a multipeptide vaccine. It also assessed immunogenicity of administration in one versus two vaccine sites. EXPERIMENTAL DESIGN: One hundred twenty-one eligible patients with resected stage IIB to IV melanoma were vaccinated with 12 MHC class I-restricted melanoma peptides to stimulate CD8+ T cells plus a HLA-DR-restricted tetanus helper peptide to stimulate CD4+ T cells, emulsified in incomplete Freund's adjuvant, with or without 110 microg GM-CSF. Among 119 evaluable patients, T-cell responses were assessed by IFN-gamma ELIspot assay and tetramer analysis. Clinical outcomes were recorded. RESULTS: CD8+ T-cell response rates to the 12 MHC class I-restricted melanoma peptides (by day 50) with or without GM-CSF were 34% and 73%, respectively (P < 0.001), by direct ELIspot assay. Tetramer analyses corroborated the functional data. CD4+ T-cell responses to tetanus helper peptide were higher without GM-CSF (95% versus 77%; P = 0.005). There was no significant difference by number of vaccine sites. Three-year overall and disease-free survival estimates (95% confidence interval) were 76% (67-83%) and 52% (43-61%), respectively, with too few events to assess differences by study group. CONCLUSIONS: High immune response rates for this multipeptide vaccine were achieved, but CD8+ and CD4+ T-cell responses were lower when administered with GM-CSF. These data challenge the value of local GM-CSF as a vaccine adjuvant in humans.

PMID: 19903780 [PubMed - in process]


J Clin Oncol. 2009 Oct 5. [Epub ahead of print]
Timed Sequential Treatment With Cyclophosphamide, Doxorubicin, and an Allogeneic Granulocyte-Macrophage Colony-Stimulating Factor-Secreting Breast Tumor Vaccine: A Chemotherapy Dose-Ranging Factorial Study of Safety and Immune Activation.

Emens LA, Asquith JM, Leatherman JM, Kobrin BJ, Petrik S, Laiko M, Levi J, Daphtary MM, Biedrzycki B, Wolff AC, Stearns V, Disis ML, Ye X, Piantadosi S, Fetting JH, Davidson NE, Jaffee EM.
Sidney Kimmel Comprehensive Cancer Center, the Departments of Oncology, Pathology, and Pharmacology, and the Programs in Pathobiology, Immunology, and Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD; Tumor Vaccine Group, University of Washington, Seattle, WA; and Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA.
PURPOSE: Granulocyte-macrophage colony-stimulating factor (GM-CSF) -secreting tumor vaccines have demonstrated bioactivity but may be limited by disease burdens and immune tolerance. We tested the hypothesis that cyclophosphamide (CY) and doxorubicin (DOX) can enhance vaccine-induced immunity in patients with breast cancer. PATIENTS AND METHODS: We conducted a 3 x 3 factorial (response surface) dose-ranging study of CY, DOX, and an HER2-positive, allogeneic, GM-CSF-secreting tumor vaccine in 28 patients with metastatic breast cancer. Patients received three monthly immunizations, with a boost 6 to 8 months from study entry. Primary objectives included safety and determination of the chemotherapy doses that maximize HER2-specific immunity. RESULTS: Twenty-eight patients received at least one immunization, and 16 patients received four immunizations. No dose-limiting toxicities were observed. HER2-specific delayed-type hypersensitivity developed in most patients who received vaccine alone or with 200 mg/m(2) CY. HER2-specific antibody responses were enhanced by 200 mg/m(2) CY and 35 mg/m(2) DOX, but higher CY doses suppressed immunity. Analyses revealed that CY at 200 mg/m(2) and DOX at 35 mg/m(2) is the combination that produced the highest antibody responses. CONCLUSION: First, immunotherapy with an allogeneic, HER2-positive, GM-CSF-secreting breast tumor vaccine alone or with CY and DOX is safe and induces HER2-specific immunity in patients with metastatic breast cancer. Second, the immunomodulatory activity of low-dose CY has a narrow therapeutic window, with an optimal dose not exceeding 200 mg/m(2). Third, factorial designs provide an opportunity to identify the most active combination of interacting drugs in patients. Further investigation of the impact of chemotherapy on vaccine-induced immunity is warranted.

PMID: 19805669 [PubMed - as supplied by publisher]



http://www.wsoctv.com/health/19540065/detail.html

Treating Lung Metastases: Aerosolized Chemotherapy
When osteosarcoma metastasizes, 85 percent of the time it goes to the lungs. Chemotherapy may be given to control the growth and/or slow the spread of the cancer. But the treatment can have serious side effects, like hair loss, fatigue and an increased risk for infection. The side effects occur because the anti-cancer drugs have to travel through the body to get at the cancer site in the lungs, damaging healthy cells along the way.Researchers are now testing a new way to treat osteosarcoma lung metastases, by using inhaled chemotherapy. The treatment, delivered through an inhaler, uses GM-CSF (granulocyte macrophage colony stimulating factor), also known as LEUKINE® (sargramostim), to stimulate the production of white blood cells that fight the tumor. Pete Anderson, MD, PhD, Cancer Researcher with MD Anderson Cancer Center in Houston, says the drug is normally given as a shot under the skin. But as white blood cells numbers increase, patients can experience a significant amount of aches and bone pain. When the treatment is given in an inhaled form, the drug goes directly into the airways and only the lung cells are affected. Thus, patients don’t experience the painful side effects.The inhaled chemotherapy is combined with another treatment, an experimental drug called mifamurtide, or L-MTP-PE. This medication binds to white blood cells and boosts their activity. Although given intravenously, it readily travels to the lungs where it, hopefully, strengthens the ability of the white blood cells to fight the tumor. Anderson says MTP-PE can cause high fever and chills, so patients are usually pretreated with medications, like ibuprofen or acetaminophen, to prevent the side effects.

[Rich66]

Ann Surg Oncol. 2009 Nov 14. [Epub ahead of print]
Local and Distant Immunity Induced by Intralesional Vaccination with an Oncolytic Herpes Virus Encoding GM-CSF in Patients with Stage IIIc and IV Melanoma.

Kaufman HL, Kim DW, Deraffele G, Mitcham J, Coffin RS, Kim-Schulze S.
Department of Surgery, Medicine and Immunology, Rush University Medical Center, Chicago, IL, USA, Howard_L_Kaufman@rush.edu.
BACKGROUND: An oncolytic herpes simplex virus engineered to replicate selectively in tumor cells and to express granulocyte-macrophage colony-stimulating factor (GM-CSF) was tested as a direct intralesional vaccination in melanoma patients. The work reported herein was performed to better characterize the effect of vaccination on local and distant antitumor immunity. METHODS: Metastatic melanoma patients with accessible lesions were enrolled in a multicenter 50-patient phase II clinical trial of an oncolytic herpesvirus encoding GM-CSF (Oncovex(GM-CSF)). An initial priming dose of 10(6) pfu vaccine was given by intratumoral injection, followed by 10(8) pfu every 2 weeks to 24 total doses. Peripheral blood and tumor tissue were collected for analysis of effector T cells, CD4(+)FoxP3(+) regulatory T cells (Treg), CD8(+)FoxP3(+) suppressor T cells (Ts), and myeloid-derived suppressive cells (MDSC). RESULTS: Phenotypic analysis of T cells derived from tumor samples suggested distinct differences from peripheral blood T cells. There was an increase in melanoma-associated antigen recognized by T cells (MART-1)-specific T cells in tumors undergoing regression after vaccination compared with T cells derived from melanoma patients not treated with vaccine. There was also a significant decrease in Treg and Ts cells in injected lesions compared with noninjected lesions in the same and different melanoma patients. Similarly MDSC were increased in melanoma lesions but underwent a significant decrease only in vaccinated lesions. CONCLUSIONS: Melanoma patients present with elevated levels of Tregs, Ts, and MDSC within established tumors. Direct injection of Oncovex(GM-CSF) induces local and systemic antigen-specific T cell responses and decreases Treg, Ts, and MDSC in patients exhibiting therapeutic responses.

PMID: 19915919 [PubMed - as supplied by publisher]





What is OncoVEXGM-CSF?

OncoVEXGM-CSF is a novel biologic drug that is a combined

• oncolytic virus (a reprogrammed virus that has been converted into a cancer-fighting agent that attacks cancerous cells, while leaving healthy cells undamaged)

and

• vaccine (a biological preparation that establishes or improves immunity to a particular disease) approach to treating advance melanoma.

The oncolytic virus component is a special strain of herpes simplex type 1 (HSV-1) virus that has been reprogrammed to infect only cancer cells. So the OncoVEXGM-CSF virus is disabled in its ability to infect normal healthy cells. The immune boosting component is the human GM-CSF gene that is put into the genetic material of the HSV-1 virus. OncoVEXGM-CSF is injected every 2 weeks into melanoma sites on the skin, just under the skin (subcutaneous) or other tumor locations that can be reached by injecting through the skin (such as lymph nodes).
GM-CSF is the name of the "control" drug that may be given to you if you take part in this research study. GM-CSF has been used in studies with patients with melanoma, but it has not been approved by the FDA for this use.

[Rich66]

Useful with GM-CSF?

J Immunol. 2009 Jul 1;183(1):137-44. Epub 2009 Jun 17.
Chemotherapeutic agents in noncytotoxic concentrations increase antigen presentation by dendritic cells via an IL-12-dependent mechanism.

Shurin GV, Tourkova IL, Kaneno R, Shurin MR.
Department of Pathology, University of Pittsburgh Medical Center, PA 15213, USA. shuringv@upmc.edu
Antineoplastic chemotherapeutic agents may indirectly activate dendritic cells (DCs) by inducing the release of "danger" signals from dying tumor cells. Whereas the direct cytotoxic or inhibitory effect of conventional chemotherapy on DCs has been reported, modulation of DC function by chemotherapeutic agents in low noncytotoxic concentrations has not yet been investigated. We have tested the effects of different classes of antineoplastic chemotherapeutic agents used in low noncytotoxic concentrations on the Ag-presenting function of DCs. We revealed that paclitaxel, doxorubicin, mitomycin C, and methotrexate up-regulated the ability of DCs to present Ags to Ag-specific T cells. Stimulation of DC function was associated with the up-regulation of expression of Ag-processing machinery components and costimulatory molecules on DCs, as well as increased IL-12p70 expression. However, the ability of DCs treated with paclitaxel, methotrexate, doxorubicin, and vinblastine to increase Ag presentation to Ag-specific T cells was abolished in DCs generated from IL-12 knockout mice, indicating that up-regulation of Ag presentation by DCs is IL-12-dependent and mediated by the autocrine or paracrine mechanisms. At the same time, IL-12 knockout and wild-type DCs demonstrated similar capacity to up-regulate OVA presentation after their pretreatment with low concentrations of mitomycin C and vincristine, suggesting that these agents do not utilize IL-12-mediated pathways in DCs for stimulating Ag presentation. These findings reveal a new mechanism of immunopotentiating activity of chemotherapeutic agents-a direct immunostimulatory effect on DCs (chemomodulation)-and thus provide a strong rationale for further assessment of low-dose chemotherapy given with DC vaccines for cancer treatment.

PMID: 19535620 [PubMed - indexed for MEDLINE]