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New therapeutic perspectives in prostate cancer Irena Manea1, B. Djavan2, C. N. Manea1, V.Cristea1, I. Coman1 1 University of Medicine and Pharmacy „Iuliu Haflieganu” Cluj-Napoca, Romania 2 Minimal Invasive and Prostate Center, New York University (NYU), New York, USA Abstract
Along with progresses in understanding the complex interactions between tumor cells and the immune response of the host and the very dynamic development of genetic engineering techniques, the newer and more efficientimmunotherapeutic techniques which generate less secondary effects are gaining more attention whenapproaching neoplasic pathology. PROVENGE (Sipuleucel-T) falls in this category and it is the first therapeutic cancervaccine to demonstrate effectiveness in patients who suffer from advanced to the late stage of the disease,asymptomatic, hormone-refractory prostate cancer.
Key words: immunotherapy, hormone-refractory prostate cancer, therapeutic antineoplastic vaccine
Spitalul Clinic Municipal Cluj-Napoca, Clinica de UrologieStr. Tæbæcarilor Nr. 11, 400139 Cluj-Napoca, Judeflul ClujTel./Fax: 0264406718e-mail: [email protected] nr. 4 / 2011 • vol 10
Revista Românæ de Urologie
decomposition under the action of an enzyme systemand turn into antigenic peptides (epitopes) on thesurface of the cellular membrane. APC are ex vivotaught to direct the immune response toward PAP .
Once they have been auto-transplanted to the patient, activated APC generate the immune message Editorial Introduction
Immunology has in time evolved from theoretical knowledge to the profoundly skeptical and fact-basedscience we know today. Immunotherapy in its manyapproaches is the highest type of the applicability ofimmunology in medicine.
Along with progresses in understanding the com- designed in the laboratory through their ability to plex interactions between tumor cells and the immune present epitopes (peptide sequences generated response of the host and the very dynamic develop- during intracellular decomposition of PAP and T lym- ment of genetic engineering techniques, the newer and phocytes). The immunologic consequence is that anti- more efficient immunotherapeutic techniques which gen specific activation of corresponding T lympho- generates less secondary effects are gaining more cytes takes place. This is the most important moment attention when approaching neoplasic pathology.
of the PROVENGE strategy against prostate cancer: T Immunotheraputic strategies in prostate cancer cells identify and destroy prostate tumor cells that include: cytokine and anticytokine therapy, activated T express the target molecule (in this case the human killer lymphocytes, dendritic cells or other antigen presenting cells, which are ex-vivo exposed to tumor Two important aspects deserve recognition: ex vivo antigens or cells. All these above mentioned are ways activation of APC eludes immunosuppression in a to stimulate the specific antitumor immunity and they tumor context, and using autologous cells excludes proved to induce a favorable clinical and biological any incompatibility in the HLA system (Human Leuko- outcome for patients with prostate cancer .
cyte Antigen) because the antigen is expressed in the PROVENGE (Sipuleucel-T) falls in this category and context of self CMH molecules (Major Histocompati- it is the first antineoplasic therapeutic vaccine ap- proved by FDA (Food and Drug Administration) in the The final product, Sipuleucel-T, contains APCs and therapy of metastatic hormone refractory prostate other cellular types involved in immune response such as T cells, natural killer cells and very small quantities ofintact PAP-GM-CSF. Each dose of PROVENGE brings tothe host’s immune system hundreds of million of acti- PROVENGE – action mechanism
vated autologous antigen presenting cells [9, 10].
PROVENGE obeys to the principles of active im- Among the techniques used to evaluate APC munotherapy and uses autologous immune cells which activation, there are the phenotyping techniques (the are trained to specifically activate one of the most evaluation of surface expressing of certain markers efficient anti-tumor immune links: T lymphocytes . such as the class II histocompatibility antigens) and the The first step of this revolutionary therapy is to functional techniques (the evaluation of the ability to perform a leukapheresis that is meant to isolate take up, process and stimulate T cells) .
peripheral mononuclear cells („peripheral blood In PROVENGE therapy, the evaluation of APC acti- mononuclear cells”, PBMC) . Among these cells, the vation is evaluated by flow cytometry studies, which antigen presenting cells (APC – macrophage, dendritic detect the CD54 differentiation marker (also known as cells, B lymphocytes) hold a key role in strategy that ICAM 1 – intracellular adhesion molecule 1). This mole- PROVENGE uses to modulate antitumor immune cule expresses itself significantly on the surface of the APC after growing in a culture along with the PAP-GM- Once isolated, APC are activated in vitro by PAP- CSF fusion protein. Moreover, in vitro studies showed GM-CSF. This is a recombinant human protein, which that CD54 positive cellular types are responsible for consists of prostatic acid phosphatase („prostatic acid taking up the antigen. In the same time, ICAM-1 plays phosphatase” PAP), linked to granulocytes-macro- an important role in activating the specific immune phage colony-stimulating factor (GM-CSF). PAP is an response as it mediates and amplifies the interactions antigen intensely expressed in prostate tumor cells, between APC and T cells. This makes the CD54 mo-le- while GM-CSF is used as immunostimulant . cule essential for an efficient cooperation of immune Antigen presenting cells activated by GM-CSF cells and is also used as a criterion to measure the exposure take over PAP, which undergo intracellular 10 Revista Românæ de Urologie
nr. 4 / 2011 • vol 10
The impact of PROVENGE therapy over the immune Clinical studies
response is complex and unpredictable. Along the PROVENGE immunotherapy has up to now been designed effect (that of destruction of the positive PAP used for over 1000 patients diagnosed with hormone cells), it also elicits humoral immune response. Sipule- refractory metastatic prostate neoplasm.
cucel-T immunomodulation is associated to measura- The adverse effects of Sipuleucel-T therapy have ble serologic levels of specific antibodies (M and G been investigated in the frame of 3 randomized multi- isotypes), which are directed against the PAP-GM-CSF center, double-blind, placebo-controlled clinic studies.
fusion protein and the prostatic acid phosphatase.
The patients included in the study have undergone Editorial
However the neutralizing humoral response is tran- three episodes of leukapherese during weeks 0, 2 and sitory; it has also been demonstrated that a T cell me- 4. Each leukapherese has been continued with PRO- diated response against the fusion protein develops VENGE or placebo administration. Inactive autologous for patients undergoing PROVENGE therapy. The clinic immune cells were administered to the witness group.
meaning of activating two sides of the specific For all patients, the curating doctor had total freedom immune response (both cellular and humoral) remains in choosing a therapeutic approach imposed by the a subject of further studies and interpretation .
evolution of the disease. The exception from this rule Hypothetically, this therapeutic vaccine can gene- was the immunosuppressive therapy,which goes rate a continuous antineoplasic immune response.
against the objective of the PROVENGE therapy to Further study is needed to confirm the activation of stimulate antitumor immune response .
All these studies showed an increase in life expec- tation for patients treated with PROVENGE. In the firstphase III trial, the average life expectation of patients PROVENGE – adverse reactions
treated with Sipuleucel-T was of 25,9 months com- This new therapeutic approach of the neoplasic pared to that of 21,4 months of the placebo treated patient also has its side effects. The majority of adverse patients. The second trial also found a bigger survival reactions is immediate and occurs after the first dose.
period for patients undergoing PROVENGE therapy.
They are usually acute infusion reactions, in relation to The third trial, IMPACT, included over 500 patients and the dose, but secondary to the cytokine imbalance, the average survival rate of patients taking Sipuleucel- and they usually improve by slowing the perfusion T was 25,8 months compared to that of 21,7 month of rate. In the majority of cases, the immediate reactions patient from the witness group. The results presented consecutive by PROVENGE administration can be in March 2010 during the Genitourinary Cancer prevented by acetaminophen or antihistaminic pre- Symposium of the American Clinic Oncology Associa- medication. Clinically, the most frequent immediate tion showed that Sipuleucel-T increased the survival reactions are nausea, vomiting, increasing fever, chills, rate to 3 years (approx. 40% more than the survival rate back pain, headache, fatigue, dyspnea, and broncho- of he placebo group: 32,1% vs. 23%) .
spasm. The majority of side effects are mild or mode- PROVENGE is being currently tested for patients rate in terms of severity. Data from controlled clinical with non-metastatic prostate adenocarcinoma and the trials shows that acute reactions (linked to the dose) show in small percent of PROVENGE treatmentpatients (3,5%) .
Among late events that occur during Sipuleucel-T Conclusions
immunomodulatory therapy are eosinophilia, rhabdo- The last decades have generated and increased myolysis, myasthenia gravis, and myositis. An impor- interest of immunology researchers which has resulted tant complication of PROVENGE administration is the in new ways of manipulating and controlling the occurrence of cerebral vascular accidents. No fatal immune system, aiming to suppress inadequate, exaggerated or altered response (as it is the case of Another important aspect is that active antioneo- auto-immune diseases, allergies and transplant rejec- plasic immunotherapy isn’t free of the dramatic side tions), to stimulate protective or corrective immune effect of the conventional therapy (both chemothe- response in case they are insufficient or depressed (as rapy and radiotherapy) that the tumoral stage would it is the case of immunodeficiency of advanced cancer).
After a decade of research and over a thousand nr. 4 / 2011 • vol 10
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Kantoff PW, Schuetz TJ, Blumenstein BA, et al. Overall survi-val analysis of a phase II randomized controlled trial of a Pox-viral-based PSA-targeted immunotherapy in metastatic cas-tration-resistant prostate cancer. J Clin Oncol. 2010;28:1099–105.
Attar RM, Takimoto CH, Gottardis MM. Castration-resistant Editorial patients that underwent this revolutionary therapy,
PROVENGE inaugurates a new era in anti-tumortherapy. As of April 2010 it becomes the firstantineoplasic therapeutic vaccine approved by FDA.
Up to now, PROVENGE therapy generated an increasein life expectancy and an improvement in the quality prostate cancer: locking up the molecular escape routes. Clin of life for patients with advanced prostate neoplasm.
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11. Vaishampayan UN, Marur S, Heilbrun LK, Cher ML, Dickow B, 1. N. C. Manea, Irena Nedelea, V. Cristea, I. Coman. Molecular Smith DW, et al. Phase II trial of capecitabine and weekly do- patterns of metastatic bone disease in prostatic adenocarcino- cetaxel for metastatic castrate resistant prostate cancer. J ma. Romanian Urology Journal 2009; 3:5-8 2. Small EJ, Fratesi P, Reese DM. et al. Immunotherapy of hor- 12. Sheikh NA, Jones LA. CD54 is a surrogate marker of antigen mone-refractory prostate cancer with antigen-loaded den- presenting cell activation. Cancer Immunol Immunother dritic cells. J Clin Oncol. 2000 Dec 1;18(23):3894–903.
Higano CS, Schellhammer PF, Small EJ. et al. Integrated data 13. Small EJ, Schellhammer PF, Higano CS, et al. Placebo-con- from 2 randomized, double-blind, placebo-controlled, Phase 3 trolled phase III trial of immunologic therapy with sipuleucel-T trials of active cellular immunotherapy with sipuleucel-T in (APC8015) in patients with metastatic, asymptomatic hormone advanced prostate cancer. Cancer. 2009 Aug 15;115(16): refractory prostate cancer. J Clin Oncol 2006;24:3089-3094 14. Goldman B, DeFrancesco L. The cancer vaccine roller Terando A, Roessler B, Mule JJ. Chemokine gene modification coaster. Nat Biotechnol 2009;27:129-139 of human dendritic cell-based tumor vaccines using a recombi- 15. Department of Health and Human Services. Parallel review nant adenoviral vector. Cancer Gene Ther. 2004;11:165–73.
of medical products. Fed Regist 2010;75(180):57045-57045 Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immu- 16. Centers for Medicare and Medicaid Services. Proposed deci- notherapy for castration-resistant prostate cancer. N Engl J sion memo for autologous cellular immunotherapy treatment of metastatic prostate cancer (CAG-00422N). March 30, 2010.
Di Lorenzo G, Buonerba C, Autorino R, et al. Castration-resis- 17. Sonpavde G, Agarwal N, Choueiri TK, Kantoff PW. Recent tant prostate cancer current and emerging treatment strate- advances in immunotherapy for the treatment of prostate gies. Drugs. 2010;70:983–1000.
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Pe mæsura progreselor în înflelegerea interacfliunilor complexe dintre celulele tumorale øi ræspunsul imun al gazdei, alæturi de dezvoltarea explozivæ a tehnicilor de inginerie geneticæ, noi modalitæfli imunoterapeutice eficienteøi cu efecte secundare cât mai mici, câøtigæ teren în abordarea patologiei neoplazice. În acest registru se înscriePROVENGE, primul vaccin terapeutic antitumoral, care øi-a dovedit eficienfla la pacienflii cu stadiu tumoral avansat,hormonorezistent.
Cuvinte cheie: cancer prostatic hormonorezistent, imunoterapia, vaccin terapeutic antineoplazic
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Concurrent Session Program Saturday 14 March 2009 9.00 to 10.30 am Session 1: Complementary Medicine and Disease Prevention Venue: Lazenby 9.00 to 9.30 am Genome health nutrigenomics and nutrigenetics: nutritional prevention of DNA damage at the population and individual level: 9.30 to 10.00 am Lipoic acid as an anti-inflammatory and neuroprotective drug for 10.00