cancer vaccine

如果預防癌症項預防感染症一樣打個疫苗就可以那該有多好 其實已免疫學的觀點來看這並非不可能，癌症細胞有其特點，與正常細胞不同，它能繼續在體內生長自有能逃過免疫細胞監視，有奇特別的抗原 實臨床際上Introduction字這個世紀初就已有這樣的觀念，這些醫學歷史發展，除了專業書籍外，一些通俗的科普書籍也多所著墨。 免疫療法廣義的來說就是利用免疫系統的細胞或分子來對抗疾病。接種疫苗可算是最早利用免疫療法的預防醫療，已知起碼出現了三百年以上，用來對抗癌症，少說也有百多年了。 十九世紀末的柯氏毒素就是利用丹毒鍊球菌製取出來，至今還是有OK432，pecibanil在使用。 迄今尚未有經過美國食品暨藥物管理局 US Food and Drug Administration (FDA)認可的免疫療法。進入21世紀，許多人相信對癌症免疫療法將會開花結果，但是還是有一大段路要努力。據說已有癌症疫苗如 CancerVax與 Melacine 進入臨床第三期實驗，就快有結論。,  過去幾年這方面頗吸引人注意，尤其是樹突細胞 (dendritic cells, DCs)運用，與疫苗的病毒載體 (viral vectors as cancer vaccines)。前者在國內的肝癌治療已有人在嘗試中。 DCs 是身體裡的天然'守衛，它主要功能在攝入、處理抗原，且呈現給其它免疫系統細胞，使得 T 細胞與產生抗體的 B 細胞所辨認。 對於 DC 瞭解的躍進，目前有臨床實驗，從血液裡分離出單核球或是具有 CD34+ 標記的前驅細胞，經培養後用癌細胞抗原給予刺激後，再注入回體內以治療。癌細胞抗原包括了 peptide-pulsed and tumor lysate-pulsed。 在國外轉移的黑色素惡性瘤的臨床試驗，已進行中，初步觀察到對一些病人可抑制腫瘤的生長。Nestle 報告約有四分之一的病人可見到成效。vitiligo 發現以腫瘤 lysate-pulsed 刺激的 DCs 有助於患者的預後。Geiger 等人在孩童腫瘤上的使用，包括 人類與癌症的爭戰自有人類以來就不曾停止，對這來自內部的叛亂細胞，瞭解愈多越明白還是有更多值得努力之處。 這幾年只要幾隻老鼠的抗癌實驗，或細胞培養的成績，就能列為重要新聞，醫學突破，登門求醫者眾。然事實上，從實驗室到人體試驗到臨床使用是條崎嶇的路，能渡過考驗真正可使用的是鳳爪鱗毛，也常須耗費是好幾年工夫。更多的藥品，早在這路上消失不見。即使能上市的藥物，也不盡然能有好成績。一些原本以為是突破的新療法，過段時日就發現有其實用性，有它的限制。醫學史裡，這樣的例子俯拾皆是。 或許由於愛滋病或癌症的重症患者，並無太多時間來等待，因此只要有任何新療法出現，就是一個新的希望。 [5] conducted a trial of tumor lysate-pulsed immature DCs in children with pediatric malignancies, and found that 4 of 10 patients who completed 3 intradermal vaccinations 2 weeks apart, including those with neuroblastoma, primitive neuroectodermal tumors, and Ewing's sarcoma, had objective responses with 3 complete remissions in chemotherapy-resistant disease. Fong and colleagues[6] described a trial of a single amino acid-modified carcinoembryonic antigen (CEA) peptide pulsed onto DCs given intravenously. In that trial, advanced colon and lung cancer patients were also treated with Flt3 ligand, a hematopoietic growth factor, resulting in a 20-fold expansion of DCs in vivo. Immunization with these CEA peptide-loaded DCs induced CD8 cytotoxic T lymphocytes that recognized tumor cells expressing endogenous CEA. Staining with peptide-major histocompatibility complex tetramers demonstrated the expansion of CD8 T cells that recognized both the native and altered epitopes and possessed an effector cytotoxic T lymphocyte phenotype (CD45RA+CD27 [-] CCR7 [-] ). After vaccination, 2 of 12 patients experienced dramatic tumor regression, 1 patient had a mixed response, and 2 had stable disease. Clinical response correlated with the expansion of CD8 tetramer-positive T cells, confirming the role of CD8 T cells in this treatment strategy.  Patients with bladder cancer were treated with immature DCs pulsed with a MAGE-3 peptide restricted to HLA-A24, resulting in 2 complete, 1 partial, and 1 mixed response in 4 heavily pretreated patients.[7] What are we to make of these data of modest clinical import, with many trials showing minor or mixed responses and the occasional dramatic regression? I believe that these early results indicate that our knowledge of how to generate and use antigen-primed DCs has lagged behind our understanding of DC biology and how they are regulated in cancer patients. Antigen-pulsed DCs were a potent antitumor treatment in mouse models, but the complex control of human immunity must be further explored to achieve better results with DC therapy in patients.  Important unanswered questions in this field are how DCs are suppressed in cancer patients, and whether "mature" DCs activated by various inflammatory and T cell-related stimuli are more effective at generating immune cells and clinical responses than "immature" DCs. A critical experiment in this regard was done by Hartgers and colleagues,[8] who showed an extraordinary autoradiogram of approximately 80% of radioactively labeled mature DC injected intradermally migrating to draining lymph nodes, whereas less than 1% to 2% of immature DCs left the injection site to localize in draining lymph node tissue. This finding, if verified in a larger number of patients, would strongly support the use of mature DCs in future trials. Treatment with DCs remains one of the most attractive and nontoxic ways to immunize patients with cancer, in spite of the fact that clinically significant responses have been few in early trials. Suppression of DCs and T Cells in Cancer Patients At a recent Immune Monitoring Workshop at the Society for Biologic Therapy Meeting in Bethesda, Maryland, D. Gabrilovich presented data on DC suppression in cancer patients. He indicated that cytokines produced by tumors such as vascular endothelial growth factor (VEGF), granulocyte-macrophage colony-stimulating factor (GM-CSF), monocyte colony-stimulating factor, interleukin (IL)-6, and IL-10 have been implicated in defective DC maturation and impairment of myelopoiesis in tumor-bearing hosts.[9]  Addition of lineage-negative, HLA-DR-positive, immature myeloid cells isolated from the peripheral blood of HLA-A2-positive cancer patients specifically inhibited production of interferon-gamma by CD8+ T cells restimulated with DCs pulsed with the specific peptide. Cancer progression has been associated with increased production of immature myeloid cells as well as immature DCs,[10] and this could be a mechanism by which progressive tumor growth may suppress antigen-specific CD8+ T cell reactivity in tumor-bearing patients. Overcoming suppression in circulating and tumor infiltrating DCs is a critical step for future development of effective tumor vaccination strategies. Innovative Vaccines and Ongoing Trials Several trials of innovative vaccines have recently begun in patients with metastatic and resected colorectal cancer. A fowlpox virus construct encoding both the CEA protein and an immune-stimulating molecule called B7.1 has been developed and has been added to 5-fluorouracil/leucovorin/CPT-11 therapy in patients with metastatic colorectal cancer. In a phase 2 pilot trial, patients randomly receive the vaccine before and during chemotherapy (with or without tetanus toxoid as a "boost") or they received the vaccine only after response to chemotherapy. The fowlpox virus is used instead of a vaccinia virus vector to avoid the strong antivaccinia response that would be observed in subjects born before the 1950s who have received a smallpox vaccine. This 100-patient pilot trial is powered to detect changes in immune response and time to progression. The trial is based on recently published data[11,12] indicating that a fowlpox vaccine encoding CEA and B7.1 used to treat 39 patients with metastatic CEA-expressing carcinomas resulted in disease stabilization in 8 of 31 patients and decrease in serum CEA in 8, who had a pretreatment elevation. In a subsequent trial by the same group, 30 patients with metastatic CEA-expressing carcinomas received GM-CSF plus the fowlpox vaccine. CEA-specific immunity was decreased compared with the previous 30 patients who received vaccine alone.  In both trials, the number of prior chemotherapy regimens was negatively correlated with immune response, whereas there was a positive correlation between the number of months from the last chemotherapy regimen and immune response. Of 25 evaluable patients receiving vaccine alone, 11 were stable, but of the 22 who received vaccine/GM-CSF, only 6 were stable and received further vaccine injections. No objective responses were seen. The strategy employed by the group developing the CEA fowlpox virus has strengths in that they are adding immune manipulation to an effective chemotherapy regimen and asking whether a pharmacodynamic end point (immune response) is affected. Some information on time to relapse and overall survival will be obtained in this small (34 patients per arm) trial to evaluate clinical benefit. Conclusions Ultimately, vaccine development should take place in the adjuvant setting (eg, in patients with minimal residual disease in which a vaccine strategy is far more likely to exert a cytostatic effect and be effective in controlling microscopic disease than mediating regression of bulk disease). This was also a consensus reached at the recent Immune Monitoring Workshop, in which the participants agreed that future cancer vaccine trials should be directed to the treatment of patients after surgical resection of disease but at high risk of relapse. A number of such pilot trials are now under way, and will likely encourage the performance of future large randomized adjuvant trials with peptide, DNA plasmid, or DC-based strategies. 參考資料： Medscape Hematology-Oncology 5(1), 2002. c 2002 Medscape, Inc. Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature. 1998;392:245-252.  Shortman K. Dendritic cells: multiple subtypes, multiple origins, multiple functions. Immunol Cell Biol. 2000;78:161-165.  Banchereau J, Palucka AK, Dhodapkar M, et al. Immune and clinical responses in patients with metastatic melanoma to CD34(+) progenitor-derived dendritic cell vaccine. Cancer Res. 2001;61:6451-6458.  Nestle FO, Alijagic S, Gilliet M, et al. Vaccination of melanoma patients with peptide- or tumor-lysate pulsed dendritic cells. Nature Med. 1998;4:328-332.  Geiger J, Hutchinson R, Hohenkirk L, McKenna E, Chang A, Mule J. Treatment of solid tumors in children with tumour-lysate-pulsed dendritic cells. Lancet. 2000;356:1163-1165.  Fong L, Hou Y, Rivas A, et al. Altered peptide ligand vaccination with Flt3 ligand expanded dendritic cells for tumor immunotherapy. Proc Natl Acad Sci U S A. 2001;98:8809-8814.  Nishiyama T, Tachibana M, Horiguchi Y, et al. Immunotherapy of bladder cancer using autologous dendritic cells pulsed with human lymphocyte antigen-A24-specific MAGE-3 peptide. Clin Cancer Res. 2001;7:23-31.  Hartgers FC, Figdor CG, Adema GJ. Towards a molecular understanding of dendritic cell immunobiology. Immunol Today. 2000;21:542-545. 9. Gabrilovich DI, Velders M, Sotomayor E, Kast VM. Mechanism of immune dysfunction in cancer mediated by immature Gr-1+ myeloid cells. J Immunol. 2001;166:5398-5403.  Almand B, Clark JL, Nikitina E, et al. Increased production of immature myeloid cells in cancer patients. A mechanism of immunosuppression in cancer. J Immunol. 2001;166:678-685.  Marshall JL, Hoyer RJ, Toomey MA, et al. Phase I study in advanced cancer patients of a diversified prime and boost vaccination protocol using recombinant vaccinia virus and recombinant nonreplicating avipox virus to elicit anti-carcinoembryonic antigen immune responses. J Clin Oncol. 2000;18:3964-3973.  von Mehren M, Arlen P, Gulley J, et al. The influence of granulocyte macrophage colony-stimulating factor and prior chemotherapy on the immunological response to a vaccine (ALVAC-CEA B7.1) in patients with metastatic carcinoma. Clin Cancer Res. 2001;7:1181-1191. Funding Information Jeffrey S. Weber, MD, PhD, has no significant financial interests to disclose. Jeffrey S. Weber, MD, PhD, Associate Professor, Department of Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California. 　 上一篇 下一篇