作者:經濟學人 2015-06-15

大致來說,對抗癌症的方法有四種,你可以開刀切除腫瘤,也可以用放射線、化療或標靶療法殺死癌細胞。現在,或許又有一種療法要加入它們的行列了,那就是「腫瘤免疫療法」。

真正的癌症疫苗難以實現,不過,新一代療法也帶來了新的可能性。它們在某方面和標靶療法很像,不同之處在於,新療法不會直接攻擊癌細胞,而是讓免疫系統攻擊它們。

專家指出,腫瘤躲避身體防衛機制的方法似乎有三。其一即為讓免疫系統無法辦識自己;其二為干擾負責發動攻擊、提供長期免疫力的T細胞;最後就是壓抑整個免疫系統的功能

許多研究人員研發出來的藥物,想截斷的就是第二種躲避方式,瞄準腫瘤細胞表面、用於干擾T細胞的「檢查點」蛋白,例如必治妥施貴寶(Bristol-Myers Squibb)的Yervoy和Opdivo、默克(Bristol-Myers Squibb)的Keytruda等。

 

現在,許多療法會瞄準一個以上的檢查點蛋白,研究亦顯示,同時使用一種以上的藥物,效果會比較好。前述藥物原本的目標是對抗黑色素瘤,但似乎也能對付其他腫瘤,例如Opdivo已獲核准,可用於治療其中一種肺癌。然而,醫學界少有奇蹟,腫瘤學界恐怕也是如此。部分病人靠Opdivo延長了性命,但對大部分病人來說,效果並不明顯,甚至是完全沒有效果

 

理論之一就是,部分腫瘤可能是使用了第一種逃脫手段,直接避免免疫系統啟動攻擊。Juno Therapeutics和Immune Design都想切斷這條逃脫路線。截斷了這條路線,也許還能強化檢查點蛋白療法的效果;結合數種免疫療法有其潛力,結合免疫與主流療法亦是如此,例如在手術之後,以免疫療法清除手術刀沒有除掉的癌細胞。新療法相當具前景,但並不便宜;Yervoy每年每人的花費為13萬美元,Opdivo約為15萬。愈來愈多藥廠投入此領域,其他藥物應該很快就會投入市場;但在富有世界人口更老更胖罹癌更多之際,問題亦逐漸浮上台面:腫瘤免疫療法能為藥廠帶來多豐厚的利潤?保險公司和政府能否負擔這樣的治療成本?(黃維德編譯)

 

原文網址:http://www.cw.com.tw/article/article.action?id=5068368#

經濟學人,英文原文網址:http://www.economist.com/news/science-and-technology/21653602-doctors-are-tryingwith-some-successto-recruit-immune-system-help?fsrc=scn%2Ffb%2Fwl%2Fpe%2Fst%2Fandthentherewerefive

 

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  • David
  • 謝謝小右 這篇我有許多話要說 卻找不到時間寫 只好慢慢回

    >部分病人靠Opdivo延長了性命,但對大部分病人來說,效果並不明顯,甚至是完全沒有效果。

    是阿 多數參加實驗的病人經過2次以上的化放療 活化的T細胞 應該都被殺光了
    在這樣的情況下還有18%的病人腫瘤有縮小
    這些病人的免疫反應是在最後一次化療後發生的
    只是受到腫瘤壓制 無法發揮功用
    可見得免疫系統隨時都在保護我們
    你的免疫系統也可以抗癌的 就怕你無視它的存在
    我知道4期癌症 不靠藥物康復的奇蹟 多半是靠免疫系統
    反而很少靠化放療痊癒的 為什麼呢?
    化放療傷害人最基本賴以生存的免疫系統
  • David
  • understanding the function and dysfunction of the immune system in cancer
    1. O. J. Finn*
    + Author Affiliations
    1. Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, USA
    1. ↵*Correspondence to: O. J. Finn, Department of Immunology, University of Pittsburgh School of Medicine, E1040 Biomedical Science Tower, Pittsburgh, PA 15261, USA. Tel: +1-412-648-9816; Fax: +1-412-648-7042; E-mail: ojfinnpitt .edu

    Abstract
    The immune system has the greatest potential for the specific destruction of tumours with no toxicity to normal tissue and for long-term memory that can prevent cancer recurrence. The last 30 years of immuno-oncology research have provided solid evidence that tumours are recognised by the immune system and their development can be stopped or controlled long term through a process known as immunosurveillance. Tumour specificity of the immune response resides in the recognition of tumour antigens. Viral proteins in tumours caused by viruses and mutated proteins from oncogenes or other genes, as well as nonmutated but abnormally expressed self proteins found on all tumours, have been shown to be good antigens and good targets for immunosurveillance. In many cancers, however, malignant progression is accompanied by profound immune suppression that interferes with an effective antitumour response and tumour elimination. Initially, most of the escape from immunosurveillance was ascribed to changes in the tumour cells themselves (loss of tumour antigens, loss of human leukocyte antigen molecules, loss of sensitivity to complement, or T cell or natural killer (NK) cell lysis), making them a poor target of an immune attack. However, it has become clear that the suppression comes from the ability of tumours to subvert normal immune regulation to their advantage. The tumour microenvironment can prevent the expansion of tumour antigen-specific helper and cytotoxic T cells and instead promote the production of proinflammatory cytokines and other factors, leading to the accumulation of suppressive cell populations that inhibit instead of promote immunity. The best described are regulatory T cells and myeloid-derived suppressor cells. Great conceptual and technical advances in the field of immuno-oncology over the past 30 years have provided us with the knowledge and techniques to develop novel immunotherapeutic approaches for the treatment of cancer. These include methods that enhance tumour immunity by blocking inhibitory pathways and inhibitory cells in the tumour microenvironment (e.g. antibodies against cytotoxic T-lymphocyte-associated antigen-4, programmed death 1 or its ligand programmed death ligand 1, or low-dose chemotherapy). Of equal importance, they include methods that can enhance the specificity of antitumour immunity by inducing the expansion of T cells and antibodies directed to well-defined tumour antigens (e.g. cancer vaccines, potent adjuvants, immunostimulatory cytokines). Even as monotherapies, these approaches are having a substantial impact on the treatment of some patients with advanced, previously untreatable, malignancies. Most exciting of all, these successes provide a rationale to expect that used in various combinations or earlier in disease, current and future immunotherapies may transform cancer treatment, improving a prognosis for many patients.

    introduction
    Most people, and scientists are no exception, measure the passing of time by acknowledging substantial events from the past and looking towards future accomplishments. Using this ‘Janus’ principle, anniversaries that celebrate substantial events or are reminders of what remains to be done can be used to monitor the progress of scientific research. One reminder of the need for progress was recently marked by the 40th anniversary of the US National Cancer Act, a Senate Bill enacted on 23 December 1971 that strengthened the authority of the National Cancer Institute and provided it with new resources to create the National Cancer Program. The US National Cancer Act was prepared and passed in recognition of the serious problem that this lethal disease was posing with its ever-increasing frequency and apparent incurability. The expectation was that an increased understanding of the basic scientific nature of the cancer would be the best road to finding a cure. The bill also recognised the timeliness of this effort, coinciding both with rapid developments in many scientific disciplines and technological advances that appeared close to allowing the biological complexity of the cancer cell to be resolved.
    Forty years later, despite many brilliant discoveries around the world in fields as diverse as genetics and molecular biology, virology, chemistry, pharmacology and others, cancer continues to elude cures. However, the pace of scientific discovery and technological developments continues to increase and, as a result, the picture of cancer is being redrawn. Immunology, long considered not to be a critical discipline for understanding cancer, has provided important new clues to cancer biology and for the first time, immune-based therapy is a focus for pharmaceutical companies developing anticancer drugs.
    Until recently, investigations into the nature of cancer focused strictly on the cancer cell and on cancer as a genetic disease. This is perfectly illustrated in the widely cited and highly popular paper by Hanahan and Weinberg [1] published in 2000 that, after reviewing a large body of cancer research, proposed six consensus characteristics (hallmarks) that could be used to define a cell as cancerous. The hallmarks comprised the capacity to sustain proliferative signaling, to resist cell death, to induce angiogenesis, to enable replicative immortality, to activate invasion and metastasis, and to avoid growth suppressors.
    A decade later, and with increased emphasis on studying cancer as a systemic disease, there is a new understanding that cancer is not one disease, but many different diseases. Therefore, to understand cancer fully, studies must move their focus from the cancer cell to the host and the microenvironment in which the cancer grows; a very important component of which is the immune system. As a result, a new picture of cancer is emerging and, in 2011, four additional hallmarks were proposed. Two of these highlight the newly recognised dual interaction between cancer and the immune system: first, the ability to avoid immune destruction which results in acute inflammation and cancer elimination, and secondly, the potential for chronic inflammation that promotes tumour growth rather than elimination [2, 3].

    interactions between the immune system and cancer
    Evidence has been accumulating since the middle of the last century, first from animal models and later from studies in cancer patients, that the immune system can recognise and reject tumours. The goal of tumour immunology has been to understand the components of the immune system that are important for tumour immunosurveillance and tumour rejection to understand how, when, and why they fail in cases of clinical disease. Immunotherapy, which involves strengthening the cancer patient's immune system by improving its ability to recognise the tumour or providing a missing immune effector function, is one treatment approach that holds promise of a life-long cure [4].
    Studies of cancer–immune system interactions have revealed that every known innate and adaptive immune effector mechanism participates in tumour recognition and control [5]. The first few transformed cells are detected by NK cells through their encounter with specific ligands on tumour cells. This leads to the destruction of some transformed cells and the uptake and processing of their fragments by macrophages and dendritic cells. In turn, these macrophages and dendritic cells are activated to secrete many inflammatory cytokines and present tumour cell-derived molecules to T- and B cells. Activation of T- and B cells leads to the production of additional cytokines that further promote activation of innate immunity and support the expansion and production of tumour-specific T cells and antibodies, respectively. The full power of the adaptive immune system leads to the elimination of remaining tumour cells and, importantly, to the generation of immune memory to specific tumour components that will serve to prevent tumour recurrence.
    Effectors of adaptive immunity, such as CD4+ helper T cells, CD8+ cytotoxic T cells, and antibodies, specifically target tumour antigens; i.e. molecules expressed in tumour cells, but not in normal cells. Tumour antigens are normal cellular proteins that are abnormally expressed as a result of genetic mutations, quantitative differences in expression, or differences in posttranslational modifications [5]. In tumour types that have a well-documented viral origin, such as cervical cancer, caused by the human papillomavirus [5], or hepatocellular carcinoma caused by the hepatitis B virus [6], viral proteins can also serve as tumour antigens and targets for antitumour immune response [7].
    The first indication that tumours carried molecules distinct from those on the normal cell of origin was derived from immunising mice with human tumours and selecting antibodies that recognised human tumour cells but not their normal counterparts. The major question was whether some, or all, of these molecules would also be recognised by the human immune system. 2011 was an important anniversary for human tumour immunology, marking 20 years since the publication by van der Bruggen et al. [8] that described the cloning of MAGE-1, a gene that encodes a human melanoma antigen recognised by patient's antitumour T cells. This was not a mutant protein; its recognition by the immune system was due to the fact that it was only expressed by transformed, malignant cells and, with the exception of testicular germ cells, was not expressed in normal adult tissue. Many similar discoveries followed, with each new molecule providing a better understanding of what might be good targets for different forms of cancer immunotherapy. Tumour antigens have been tested as vaccines, as targets for monoclonal antibodies, and as targets for adoptively transferred cytotoxic T cells. There is a wealth of publications from preclinical studies targeting these antigens and results from phase I/II clinical trials. Recently, these studies were critically reviewed and a list of tumour antigens with the largest body of available data compiled [9]. The goal was to encourage faster progress in the design, testing, and approval of immunotherapeutic reagents that incorporate or target the most promising antigens.
    Antitumour immune responses in animal models and cancer patients have contributed to the resurgence of the immunosurveillance theory; albeit one that has been modified to encompass different observed outcomes. Instead of defining immunosurveillance as the process by which cancer is recognised and eliminated and a diagnosis of cancer to represent the failure of this process, it is now recognised that in different individuals and with different cancers, the process can have at least three different but related outcomes: elimination, equilibrium, and escape [10]. A highly immunogenic tumour in a highly immunocompetent individual will result in optimal stimulation of the innate immune system leading to the production of highly immunostimulatory cytokines, acute inflammation, activation of a large number of T- and B cells, and prompt elimination of the arising tumour. With a less immunocompetent individual and/or less immunogenic tumour, however, there might not be a complete elimination leading to the survival of some cancer cells that nevertheless remain under immunosurveillance. Over a prolonged period of time, the slow growth of the tumour would be accompanied by repeated activation of the immune system and elimination of some tumour cells, followed by further cycles of tumour regrowth and immune-mediated destruction. This period, when the tumour is present but not yet a clinical disease, is known as equilibrium. The equilibrium phase could be life-long, thus mimicking elimination, or be disturbed by changes in the tumour that allow it to avoid immunosurveillance or changes in the immune system that weaken its capacity for tumour surveillance. Either change ultimately leads to tumour escape (Figure 1).
    To date, most studies of tumour/immune system interactions have been performed after cancer has been diagnosed, i.e. in the escape phase of immunosurveillance. This particular phase is characterised by an increase in previously unknown immunosuppressive cells, such as regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSC), immunosuppressive cytokines derived from Treg, MDSC, and tumour cells and poorly functional effector T cells expressing molecules capable of preventing T-cell activation [11–13].

    immunotherapy: old and new
    In the past, immunotherapy was referred to as ‘passive’ (e.g. the infusion of preformed immune effectors, such as antibodies, cytokines, or activated T cells, NK cells, or lymphokine-activated killer cells), presumably acting directly on the tumour and independent of the immune system or ‘active’ (e.g. vaccines), designed to activate and therefore be dependent on the patient's immune system.
    However, with increased understanding of the importance of multiple immune effector mechanisms for tumour elimination and of the immunosuppressive forces that influence these mechanisms in the tumour microenvironment, it has since become clear that both passive and active immunotherapies depend on the patient's immune system for long-term tumour control or complete tumour elimination.
    By directly targeting specific antigens expressed by cancer cells, anticancer monoclonal antibodies are a well-established class of immunotherapeutic agent; more than a dozen of which have been approved by the Food and Drug Administration as standard treatment of several different cancers, including trastuzumab for breast cancer and retuximab for B-cell lymphoma [4]. Although the mechanism of their direct antitumour action has been well studied and is clearly responsible for transient remissions in patients receiving this therapy, cure rates are still very low. The potential of these antibodies is drastically undermined by their administration relatively late in the disease course, when the patient's immune system is largely compromised. Under more optimal conditions, antibody treatment might result not only in the direct cytostatic or cytotoxic effect on the tumour cell, but also in the loading of antibody-bound tumour antigens onto antigen presenting cells (APC) in the tumour microenvironment. The resultant cross-presentation to antitumour T- and B cells could result in additional antibodies to these antigens being produced, and propagation of the immune response at the tumour site would maintain tumour elimination long after the infused monoclonal antibody is gone. Not only would the response change from a monoclonal antibody against a single epitope to a polyclonal response to multiple epitopes, thus avoiding antigen-negative tumour escape, but the effector T-cell response would also generate memory.
    The same scenario could be predicted for adoptively transferred T cells. Unlike antibodies, transferred T cells persist longer and may provide a memory response [14]; however, as long as the memory response is restricted to one clone, or a limited number of clones, then antigen-negative tumours will be able to escape. In addition, cancer vaccines encounter large numbers of immunosuppressive Treg and MDSC in circulation, as well as immunosuppressive cell-derived soluble products that flood the lymph nodes, preventing maturation of APCs and activation of T cells. Even when vaccines are delivered in the context of ex vivo matured and activated dendritic cells, their ability to activate T cells is compromised by the high-level expression of various molecules on T cells that block this process.
    The scenarios proposed above present a rather bleak picture of the potential of immunotherapy to achieve the cure for cancer that has eluded standard therapy [15]. Interestingly, failures of some standard therapies are beginning to be ascribed to their inability to activate the patient's immune system [16]. However, rather than seeing the picture as a deterrent, it should be considered as a road map, providing at least two major directions for new developments in immunotherapy.
    The first direction is to continue using the old classes of immunotherapy that target the cancer directly, but to use them in combination with therapies that target the immune system in the tumour microenvironment, such as cytokines, suppressors of Treg or MDSC activity, or antibodies that modulate T-cell activity. The recently approved antibody, ipilimumab, which acts to sustain cytotoxic T-cell activity by augmenting T-cell activation and proliferation, is one example of such an immunomodulatory agent [17].
    The other direction is to use immunotherapies, both old and new, for preventing cancer in individuals at high risk [18]. Studies of the tumour microenvironment are providing information about immunosurveillance of tumours from early premalignant lesions to more advanced dysplastic lesions to cancer. At each step, tumour-derived and immune system-derived components have a unique composition that will have distinct effects on immunotherapy. Because these premalignant microenvironments are less developed and immunosuppression is less entrenched, it should be easier to modulate towards the elimination of abnormal cells.
    The lessons learnt from past accomplishments suggest that in the future, well-designed immunotherapies, administered at the right stage of tumour progression, have the potential to significantly change the ongoing immune response in the tumour microenvironment from tumour-promoting to tumour-rejecting (Figure 1).


    http://annonc.oxfordjournals.org/content/23/suppl_8/viii6.full
  • prajana
  • 感謝David時常提供癌症相關資訊。
  • 感謝 prajana 代替我們道謝~

    小右or姐姐 於 2015/07/17 21:47 回覆

  • David
  • 這篇文章提出在腦轉移病人打anti CTLA4 藥品後
    免疫細胞在腦部和癌細胞作戰的醫學證據
    所有證據都顯示免疫細胞可以進入腦部

    CTLA-4 Blockade With Ipilimumab Induces Significant Clinical Benefit in a Female With Melanoma Metastases to the CNS

    Summary

    Background: A 63-year-old female presented to her primary physician with numbness and weakness in her left leg, which progressed over several days to involve her entire lower extremities. MRI of the spine and brain revealed multiple metastases. The patient received ipilimumab and after 3 months experienced intermittent confusion and focal seizures.
    Investigations: Electroencephalogram and MRI scans of the spine and brain, followed by surgical removal of a left frontal cortical brain metastasis and subsequent histological and pathological analyses. Diagnosis Metastatic melanoma from an unknown primary tumor.
    Management: The patient was treated with ipilimumab on a compassionate-use program and dexamethasone, celecoxib, and levetiracetam to treat the symptoms and seizures. Postoperative stereotactic radiosurgery was initiated.

    The Case

    A 63-year-old female presented to her primary physician with numbness and weakness in her left leg, which progressed over several days to involve her entire lower extremities. The patient’s medical history included removal of a benign bone tumor as a child and the removal of a squamous cell skin cancer within the few weeks before presentation. There was no patient history of primary melanoma, but her mother and daughter had both had melanoma, which in both cases had been successfully treated by local excision. A spinal MRI scan revealed metastatic disease involving the spinal cord at C5 and T3, and an 8 mm focal-enhancing T1 metastasis. A brain MRI scan revealed four metastases, including a dominant 3.5 cm × 2.2 cm × 2.7 cm lesion in the right posterior parietal cortex. Since the patient had a symptomatic metastasis in a surgically accessible location, a neurosurgical evaluation was conducted and this determined that function of her legs could be restored by removal of the tumor. In addition, resection of the tumor would allow the associated edema to resolve. The parietal cortex lesion was surgically removed revealing metastatic melanoma. As the patient presented with three brain metastases and no evidence of leptomeningeal disease, she was offered either whole-brain radiation therapy (WBRT), or WBRT plus stereotactic radiosurgery (SRS), or SRS alone. Given the relatively low efficacy of WBRT in melanoma and her reluctance to undergo initial WBRT, SRS alone[1] was used to treat the gross lesions and tumor bed. The patient received radiation to her spine and SRS to the brain lesions. Following radiation, she received temozolomide orally at 200 mg/m2 daily on days 1-5 of a 28-day cycle for 3 months. Restaging by chest, abdomen, pelvis, and head and spine MRIs revealed moderate disease progression in the lungs and central nervous system (CNS).

    The patient then received compassionate-use ipilimumab (MDX-010, Bristol-Myers Squibb, New York, NY and Medarex Inc. Princeton, NJ), a fully human monoclonal antibody directed against CTLA-4, a key negative regulator of T-cell-mediated immune responses.[2] (See Supplementary Figure 1 online). Ipilimumab was administered intravenously at 3 mg/kg once every 3 weeks for four doses with maintenance dosing anticipated every 12 weeks. A month after starting ipilimumab treatment, the patient complained of decreased sensation in her left thigh. A repeat spinal MRI revealed slight edema surrounding the previously identified cord metastases. These symptoms subsided over the following 2 weeks without additional intervention while the patient remained under observation. At 3 months after treatment initiation, she began to experience complex partial seizures characterized by confusion, aphasia, gait apraxia, and automatisms (lip smacking and fidgeting). An electroencephalography (EEG) was consistent with interictal activity arising from the left frontal lobe and a brain MRI confirmed moderate edema surrounding the known metastases, with evidence of central tumor necrosis. The patient was treated with celecoxib (200 mg by mouth twice a day) and levetiracetam (1,500 mg by mouth twice a day), which resulted in an immediate and marked improvement in symptoms.

    Over the following 3 months, the patient experienced intermittent confusion. Edema surrounding pre-existing CNS tumors was noted (Figure 1) and EEG revealed focal epileptic activity. Dexamethasone was added to the regimen and titrated (≤4 mg twice daily) to complete the resolution of symptoms. The patient returned to baseline function within 2 weeks of dexamethasone initiation. Several MRI scans of her spine over the following 6 months showed waxing and waning of the edema surrounding known spinal metastases with involution and complete disappearance of tumors in some areas (Figure 2). Her performance status continued to improve, such that she was able to play two rounds of golf each week while previously she had been home bound.

    At 7 months after the initiation of treatment with ipilimumab, the patient experienced recurrent confusion with evidence of edema and focal seizure activity associated with a left frontal cortical brain metastasis. Surgical removal of this lesion revealed focal areas of necrosis with marked infiltration of the tumor by lymphocytes and an abundance of melanophages throughout (Figures 3 and 4). This concerted immune- mediated response was dominated by CD8+ lymphocytes, with a paucity of FoxP3+ regulatory cells in the infiltrate of the brain lesion.


    This patient did not have an objective response as defined by standard Response Evaluation Criteria in Solid Tumors (RECIST), although she experienced stable disease for 7 months after starting ipilimumab and lived for 2 years following her initial presentation.

    Discussion of Diagnosis

    CNS metastases occur in more than 50% of patients diagnosed with advanced melanoma.[3] The prognosis for these patients is poor, with a median survival of 4.[4] months and a 5-year survival rate of approximately 3%.[4] In a retrospective analysis of 702 patients with melanoma who presented with brain metastases, 94.5% had a CNS-related cause of death.[5] Even when systemic therapy produces responses to visceral metastases, the CNS is a frequent site of tumor recurrence. For example, approximately 50% of patients with metastatic melanoma who initially responded to biochemotherapy regimens developed recurrence or progression in the CNS.[6] Furthermore, single and multiple brain lesions can be treated with a combination of surgery and radiation, but tumor progression in the CNS is frequent even in heavily pretreated individuals, indicating the presence or recurrence of micrometastases that go undetected and are unaffected by the current standard therapies.

    Pathological review of this case revealed a predominantly cytotoxic antitumor immune response in the CNS following CTLA-4 blockade. The tumor destruction associated with this immune response correlated with the radiographic findings. The paucity of regulatory T cells in the infiltrate, as assayed by FoxP3 immunohistochemistry, also supports the mechanism for effective immune recognition of tumor. This is consistent with experimental findings that suggest that anti-CTLA-4 blockade causes a relative decrease in the frequency of regulatory T cells through preferential expansion of cytotoxic CD8+ T cells2 or by abrogating the function of regulatory T cells.[7] In this case, the pathological changes in the resected melanoma specimen following treatment suggest that such processes might also be applicable to CNS malignancies despite the inability of most drugs to penetrate the blood–brain barrier. This case provides rare evidence that immunotherapy with ipilimumab to affect CTLA-4 blockade can result in the effective treatment of tumors involving the CNS. Clinical features that should alert the clinician to the possibility of ipilimumab-mediated antitumor immune activity in the CNS are listed in Box 1 . The surgical pathology demonstrates the ability of immune effector cells to home to sites of CNS disease and contribute to tumor necrosis and edema; processes that, importantly, were associated with an improved outcome and extended survival in this patient.

    Treatment and Management

    MRI staging of both the brain and spinal cord provides a useful radiographic correlate to the pathology and clinical course. The disease stabilization and performance status resulting from ipilimumab treatment far exceeded the expectations for patients presenting with multiple CNS metastases from advanced melanoma. It is worth noting that although this patient received ipilimumab through a single-patient compassionate protocol at a dosage that had previously demonstrated clinical activity (3 mg/kg), subsequent multicenter phase II and III trials examined ipilimumab at 10 mg/kg for both induction and maintenance therapy.

    A significant lymphocytic infiltrate has occasionally been demonstrated in primary tumors of the CNS.[8] Dendritic-cell vaccination strategies in animal models of melanoma and in patients with glioblastoma multiforme have resulted in the intratumoral infiltration of immune effector cells, thus, suggesting a new way to approach the treatment of CNS malignancies.[9,10] Although data are promising, it is becoming apparent that additional problems need to be addressed, such as the role of tumor-infiltrating immune regulatory cells in the CNS.[11,12]

    An effective, systemic therapy that gives durable responses or disease stabilization simultaneously in CNS and non-CNS sites is needed. The enthusiasm for evaluating immune therapies for these patients, however, has been limited by the postulation/assumption that the CNS is an immune-privileged site. The blood-brain barrier offers mechanical protection and controls molecular transport between the vasculature and CNS.[13] Even when systemic therapies are effective, the CNS is a frequent site of treatment failure.[14] It is, therefore, not expected that immune components will reach brain metastases successfully and elicit a meaningful response.

    Ipilimumab is under investigation to treat several types of cancers, with a particular focus on melanoma. In preclinical murine studies, CTLA-4 blockade using monoclonal antibodies has demonstrated antitumor activity.[2] Results of early trials in patients with metastatic melanoma show that ipilimumab alone or with other therapies (i.e. vaccines or chemotherapy) is generally well tolerated and results in objective responses and disease stabilization.[15-17] Pathology analysis from a subset of patients whose pre-existing metastases were biopsied following treatment with ipilimumab revealed infiltrates of CD4+, CD8+, and CD20+ lymphocytes, neutrophils, and extensive (>90%) tumor necrosis.[14] Potential effects of CTLA-4 blockade on melanoma metastases to the CNS have been unclear; however, this case suggests that the antitumor effect may be executed via CNS tumor infiltration by CD8+ lymphocytes.

    Conclusions

    This case describes pathological evidence of immune-mediated inflammation and edema with extensive tumor disruption and evidence of foci of necrosis within the CNS in response to ipilimumab therapy in a patient with advanced melanoma. Investigation of CTLA-4 blockade and other immune therapies to treat CNS metastases should be a focus of further clinical investigation.

    Supplementary information in the form of a figure is available on the Nature Clinical Practice Oncology website.
  • 美樂地

  • 在下面貼的連結裡, 人體試驗委員會folder的會議記錄, 其實醫院好像針對各種用藥, 都有相關的人體試驗, (而且可以點進去看呢)

    http://www.kfsyscc.org/zh-tw/research-and-edu/
  • David
  • 重點翻譯一下

    因為有血腦障壁 許多藥品都進不到腦裡

    醫界以前認為 腦是特權區域 不期待免疫細胞可以進入腦 這報告說明這個假設是錯誤的

    (我讀過另一篇報告 研究免疫細胞如何進入腦內 方法大致是 免疫細胞分泌促進發炎的細胞介素

    讓血腦障壁細胞間的細縫張開 從細縫間專鑽入腦內

    這方法與當你皮膚割傷後 免疫細胞如何重鑽出微血管 到受傷的皮膚層一樣)

    The enthusiasm for evaluating immune therapies for these patients, however, has been limited by the postulation/assumption that the CNS is an immune-privileged site. The blood-brain barrier offers mechanical protection and controls molecular transport between the vasculature and CNS.[13] Even when systemic therapies are effective, the CNS is a frequent site of treatment failure.[14] It is, therefore, not expected that immune components will reach brain metastases successfully and elicit a meaningful response.



    病人打了anti CTLA4 藥品後 抑制免疫反應的regulatory T cells減少 毒殺型(CD8+) T cells 增加

    免疫反應能有效的破壞腫瘤

    The tumor destruction associated with this immune response correlated with the radiographic findings. The paucity of regulatory T cells in the infiltrate, as assayed by FoxP3 immunohistochemistry, also supports the mechanism for effective immune recognition of tumor.

    This is consistent with experimental findings that suggest that anti-CTLA-4 blockade causes a relative decrease in the frequency of regulatory T cells through preferential expansion of cytotoxic CD8+ T cells2 or by abrogating the function of regulatory T cells.



    這個病例記錄anti CTLA4藥品引起免疫反應 造成的發炎水腫和大規模腫瘤破壞



    This case describes pathological evidence of immune-mediated inflammation and edema with extensive tumor disruption and evidence of foci of necrosis within the CNS in response to ipilimumab therapy in a patient with advanced melanoma.
  • David
  • 仔細看這個病例會發現病人是先做放療(電腦刀) 再打Yervoy
    放療破壞腫瘤 同時死去的癌細胞會激起免疫反應
    Yervoy讓毒殺型(CD8+) T cells 順利繁衍增生
    不受腫瘤抑制免疫反應的regulatory T cells影響
    唯一遺憾的是當時Anti PD1藥品尚未出現
    少了Anti PD1藥品 免疫反應無法持續下去
    最後腫瘤反撲 病人於兩年後辭世
  • David
  • 免疫治療要有效 一定要包括 Anti PD1藥品
    放療可以破壞腫瘤 同時死去的癌細胞會激起免疫反應
    放療是很好的輔助免疫治療的方式
  • David
  • 2015: The Year of Anti-PD-1/PD-L1s Against Melanoma and Beyond

    The history of clinical oncology has witnessed several revolutionary therapeutic advances that have significantly improved cancer care. These have included the introduction of cisplatin in the 1970s for testicular and ovarian cancers, the taxanes in the 1990s for breast and other solid tumors, targeted therapy with anti-HER2 for breast cancer and c-Kit inhibitors for chronic myeloid leukemia and other cancers at the start of this millennium. Each of these treatments has revolutionized outcomes for patients with various types of cancer. Today, we are at the start of a new era in cancer care — that of immunotherapy. The approval of sipuleucel-T for the treatment of prostate cancer in 2010 and ipilimumab (anti-CTLA-4) for advanced melanoma in 2011 was the first notable success in the immunotherapy of cancer. After almost three years from the approval of the first checkpoint inhibitor (ipilimumab), the good news is not over. Quite the contrary, we are only at the beginning and, notably, these advances do not relate just to the treatment of melanoma. Immunotherapy has become the fourth pillar of cancer treatment alongside surgery, radiotherapy and chemotherapy (including targeted therapy). This can be attributed primarily to the impact that another group of checkpoint inhibitors, the anti-PD-1/PD-L1 agents, is having on the treatment of various malignancies.

    As with anti-CTLA-4, the anti-PD-1/PD-L1 story starts with melanoma. Data from a large phase I study with pembrolizumab (Robert et al., 2014a

    , Robert et al., 2014b

    ) led to its approval by the US Food and Drug Administration (FDA) in September 2014 for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. This study of 411 patients showed that pembrolizumab resulted in an overall response rate (ORR) of 34%, a median progression-free survival (PFS) of 5.5 months, and overall survival (OS) rates of 69% at one year and 62% at 18 months. Moreover, a randomized phase II trial with pembrolizumab at two different dosages (2 mg/kg or 10 mg/kg every three weeks) in advanced melanoma refractory to previous ipilimumab therapy showed that both doses improved PFS compared with investigator choice chemotherapy (Ribas et al., 2014

    ). In fact, the 6-month PFS was 34% with pembrolizumab 2 mg/kg, 38% with pembrolizumab 10 mg/kg and 16% with chemotherapy, while the 9-month PFS was 24%, 29% and 8% respectively. The ORR in the three groups was 21%, 25% and 4%, respectively.

    More recently, in December 2014, another anti-PD-1, nivolumab, was approved by the FDA for patients with advanced melanoma with the same indication as pembrolizumab. Data from a large phase I trial with nivolumab showed an ORR of 32% and 1, 2, 3, and 4-year OS rates of 63%, 48%, 42%, and 32%, respectively. In addition, data from a phase III study in patients with metastatic melanoma previously treated with ipilimumab reported that nivolumab had an ORR of 32% compared with 11% with the chemotherapy control arm (D'Angelo et al., 2014

    ). Nivolumab was also compared to chemotherapy in another randomized phase III trial in which untreated patients with advanced BRAF wild-type melanoma received either nivolumab or dacarbazine. The ORR was 40.0% in the nivolumab group versus 13.9% in the dacarbazine group. At 1 year, the OS was 73.0% in the nivolumab group compared with 42.1% in the dacarbazine group. Median PFS was 5.1 months in the nivolumab group versus 2.2 months in the dacarbazine group (Robert et al., 2014a

    , Robert et al., 2014b

    ).

    Considering historical data with a typical median OS of 6.2 months and 1-year OS rate of 25.5% and 1 and 2-year OS rates of 45% and 24% obtained with ipilimumab therapy in the treatment of advanced melanoma, the results achieved with anti-PD-1 therapy represent a terrific improvement in clinical benefit for these patients. Moreover, these data obtained in melanoma patients are just the start.

    OS data from a phase I study of nivolumab in solid tumors were particularly encouraging, even in patients with non-small-cell lung cancer (NSCLC), with a median OS of 9.6 months, 1-year OS of 42% and 2-year OS of 24%. Moreover, in a phase II study in patients with advanced, refractory NSCLC, nivolumab was associated with an ORR of 15% and a median OS of 8.2 months (Ramalingam et al., 2014

    ). Historically, these patients have ORRs of between 2 and 8% and a median OS of about 5 months. The estimated 1-year survival rate was 41%, which also compares favorably with historical data for patients with third-line squamous cell NSCLC of 1-year OS rates of 5.5–18%. Pembrolizumab has also shown interesting results in NSCLC. In the NSCLC expansion cohort of a phase I trial, pembrolizumab treatment resulted in an ORR of 21%. The median PFS in treatment-naïve patients was 27 weeks and 6-months OS was 86%, while in pretreated patients median PFS was 10 weeks and 6-months OS was 59% (Garon et al., 2014

    ).

    Interesting preliminary results have also been reported for urothelial bladder cancer (UBC) and triple negative breast cancer (TNBC). In patients with platinum-pretreated, metastatic UBC, the ORR obtained with an anti-PD-L1 antibody (MPDLA3280) was between 11% and 43%, depending on the level of PD-L1 (Powles et al., 2014

    ). In patients with heavily pretreated advanced TNBC, pembrolizumab achieved an ORR of 18.5% with a durable response (median response duration was not reached) (Nanda et al., 2014

    ).

    Anti-PD-1 therapy has also achieved interesting results in patients with hematological malignancies. In a small phase I study that enrolled 23 patients with relapsed or refractory Hodgkin's lymphoma that had already been heavily treated, nivolumab resulted in a clinical benefit in all patients; the ORR was 87% (20/23), with 17% having a complete response and 70% a partial response. The remaining three patients (13%) all had stable disease (Ansell et al., 2014

    ). PFS at 6 months was 86%. In another phase Ib study, pembrolizumab also demonstrated promising antitumor activity in patients with heavily pretreated Hodgkin's lymphoma, with a 21% complete remission rate and an ORR of 65% (Craig et al., 2014

    ).

    What can we expect during 2015? New data in other types of cancer are surely expected. Studies with anti-PD-1/PD-L1 are ongoing in gastric cancer, small-cell lung cancer, glioblastoma, colorectal cancer, Merkel cell carcinoma and others. There are also likely to be more data concerning the role of PD-L1 as a predictive marker, even though data from phase III studies in melanoma seem to refute such a role. We will also see more important news on the potential of anti-PD-1/PD-L1s in combination with other approaches, including other immunotherapies (e.g. checkpoint inhibitors), radiotherapy, chemotherapy and targeted agents. We are observing the beginning of another new era in the fight against cancer: that of anti-PD-1/PD-L1 therapy.

    Source:
    http://www.ebiomedicine.com/article/S2352-3964(15)00034-1/fulltext
  • David
  • 在美國政府癌症機構(NCI) 推廣的T細胞療法(CAR-T)
    已經進步到用基因改造在T細胞加上能辨識癌症的受體
    因為是基因改造 T細胞繁衍的世世代代代都能辨識癌症
    NCI 稱它為 “A Living Drug”

    幾家biotech 公司已經在NCI 的技術 上改良 第三代CAR-T已經在雸研究中
    這將是癌症歷史上為最客制化也是最昂貴的癌症治療技術


    CAR T-Cell Therapy: Engineering Patients’ Immune Cells to Treat Their Cancers

    For years, the cornerstones of cancer treatment have been surgery, chemotherapy, and radiation therapy. Over the last decade, targeted therapies like imatinib (Gleevec®) and trastuzumab (Herceptin®)—drugs that target cancer cells by homing in on specific molecular changes seen primarily in those cells—have also emerged as standard treatments for a number of cancers.

    And now, despite years of starts and stutter steps, excitement is growing for immunotherapy—therapies that harness the power of a patient’s immune system to combat their disease, or what some in the research community are calling the “fifth pillar” of cancer treatment.

    One approach to immunotherapy involves engineering patients’ own immune cells to recognize and attack their tumors. And although this approach, called adoptive cell transfer (ACT), has been restricted to small clinical trials so far, treatments using these engineered immune cells have generated some remarkable responses in patients with advanced cancer.

    For example, in several early-stage trials testing ACT in patients with advanced acute lymphoblastic leukemia (ALL) who had few if any remaining treatment options, many patients’ cancers have disappeared entirely. Several of these patients have remained cancer free for extended periods.

    Equally promising results have been reported in several small trials involving patients with lymphoma.

    These are small clinical trials, their lead investigators cautioned, and much more research is needed.

    But the results from the trials performed thus far “are proof of principle that we can successfully alter patients’ T cells so that they attack their cancer cells,” said one of the trial's leaders, Renier J. Brentjens, M.D., Ph.D., of Memorial Sloan Kettering Cancer Center (MSKCC) in New York.

    “A Living Drug”

    Adoptive cell transfer is like “giving patients a living drug,” continued Dr. Brentjens.

    That’s because ACT’s building blocks are T cells, a type of immune cell collected from the patient’s own blood. After collection, the T cells are genetically engineered to produce special receptors on their surface called chimeric antigen receptors (CARs). CARs are proteins that allow the T cells to recognize a specific protein (antigen) on tumor cells. These engineered CAR T cells are then grown in the laboratory until they number in the billions.

    The expanded population of CAR T cells is then infused into the patient. After the infusion, if all goes as planned, the T cells multiply in the patient’s body and, with guidance from their engineered receptor, recognize and kill cancer cells that harbor the antigen on their surfaces.

    This process builds on a similar form of ACT pioneered by Steven Rosenberg, M.D., Ph.D., and his colleagues from NCI’s Surgery Branch for patients with advanced melanoma.

    The CAR T cells are “much more potent than anything we can achieve” with other immune-based treatments being studied, said Crystal Mackall, M.D., of NCI’s Pediatric Oncology Branch (POB).

    Even so, investigators working in this field caution that there is still much to learn about CAR T-cell therapy. But the early results from trials like these have generated considerable optimism.

    CAR T-cell therapy eventually may “become a standard therapy for some B-cell malignancies” like ALL and chronic lymphocytic leukemia, Dr. Rosenberg wrote in a Nature Reviews Clinical Oncology article.

    A Possible Option Where None Had Existed

    More than 80 percent of children who are diagnosed with ALL that arises in B cells—the predominant type of pediatric ALL—will be cured by intensive chemotherapy.

    For patients whose cancers return after intensive chemotherapy or a stem cell transplant, the remaining treatment options are “close to none,” said Stephan Grupp, M.D., Ph.D., of the Children’s Hospital of Philadelphia (CHOP) and the lead investigator of a trial testing CAR T cells primarily in children with ALL. This treatment may represent a much-needed new option for such patients, he said.

    Trials of CAR T cells in adults and children with leukemia and lymphoma have used T cells engineered to target the CD19 antigen, which is present on the surface of nearly all B cells, both normal and cancerous.

    In the CHOP trial, which is being conducted in collaboration with researchers from the University of Pennsylvania, all signs of cancer disappeared (a complete response) in 27 of the 30 patients treated in the study, according to findings published October 16 in the New England Journal of Medicine.

    Nineteen of the 27 patients with complete responses have remained in remission, the study authors reported, with 15 of these patients receiving no further therapy and 4 patients withdrawing from the trial to receive other therapy.

    According to the most recent dataExit Disclaimer from a POB trial that included children with ALL, 14 of 20 patients had a complete response. And of the 12 patients who had no evidence of leukemic cells, called blasts, in their bone marrow after CAR T-cell treatment, 10 have gone on to receive a stem cell transplant and remain cancer free, reported the study’s lead investigator, Daniel W. Lee, M.D., also of the POB.

    Even so, investigators working in this field caution that there is still much to learn about CAR T-cell therapy. But the early results from trials like these have generated considerable optimism.

    CAR T-cell therapy eventually may “become a standard therapy for some B-cell malignancies” like ALL and chronic lymphocytic leukemia, Dr. Rosenberg wrote in a Nature Reviews Clinical Oncology article.

    A Possible Option Where None Had Existed

    More than 80 percent of children who are diagnosed with ALL that arises in B cells—the predominant type of pediatric ALL—will be cured by intensive chemotherapy.

    For patients whose cancers return after intensive chemotherapy or a stem cell transplant, the remaining treatment options are “close to none,” said Stephan Grupp, M.D., Ph.D., of the Children’s Hospital of Philadelphia (CHOP) and the lead investigator of a trial testing CAR T cells primarily in children with ALL. This treatment may represent a much-needed new option for such patients, he said.

    Trials of CAR T cells in adults and children with leukemia and lymphoma have used T cells engineered to target the CD19 antigen, which is present on the surface of nearly all B cells, both normal and cancerous.

    In the CHOP trial, which is being conducted in collaboration with researchers from the University of Pennsylvania, all signs of cancer disappeared (a complete response) in 27 of the 30 patients treated in the study, according to findings published October 16 in the New England Journal of Medicine.

    Nineteen of the 27 patients with complete responses have remained in remission, the study authors reported, with 15 of these patients receiving no further therapy and 4 patients withdrawing from the trial to receive other therapy.

    According to the most recent dataExit Disclaimer from a POB trial that included children with ALL, 14 of 20 patients had a complete response. And of the 12 patients who had no evidence of leukemic cells, called blasts, in their bone marrow after CAR T-cell treatment, 10 have gone on to receive a stem cell transplant and remain cancer free, reported the study’s lead investigator, Daniel W. Lee, M.D., also of the POB.

    “Our findings strongly suggest that CAR T-cell therapy is a useful bridge to bone marrow transplant for patients who are no longer responding to chemotherapy,” Dr. Lee said.

    Similar results have been seen in phase I trials of adult patients conducted at MSKCC and NCI.

    In findings published in February 2014, 14 of the 16 participants in the MSKCC trial treated to that point had experienced complete responses, which in some cases occurred 2 weeks or sooner after treatment began. Of those patients who were eligible, 7 underwent a stem cell transplant and are still cancer free.

    The NCI-led trial of CAR T cells included 15 adult patients, the majority of whom had advanced diffuse large B-cell lymphoma. Most patients in the trial had either complete or partial responses, reported James Kochenderfer, M.D., and his NCI colleagues.

    “Our data provide the first true glimpse of the potential of this approach in patients with aggressive lymphomas that, until this point, were virtually untreatable,” Dr. Kochenderfer said. [NCI Surgery Branch researchers have also reported promising resultsExit Disclaimer from one of the first trials testing CAR T cells derived from donors, rather than the patients themselves, to treat leukemia and lymphoma.]

    Other findings from the trials have been encouraging, as well. For example, the number of CAR T cells increased dramatically after infusion into patients, as much as 1,000-fold in some individuals. In addition, after infusion, CAR T cells were detected in the central nervous system, a so-called sanctuary site where solitary cancer cells that have evaded chemotherapy or radiation may hide. In two patients in the NCI pediatric trial, the CAR T-cell treatment eradicated cancer that had spread to the central nervous system.

    If CAR T cells can persist at these sites, it could help fend off relapses, Dr. Mackall noted.

    Managing Unique Side Effects

    CAR T-cell therapy can cause several worrisome side effects, perhaps the most troublesome being cytokine-release syndrome.

    The infused T cells release cytokines, which are chemical messengers that help the T cells carry out their duties. With cytokine-release syndrome, there is a rapid and massive release of cytokines into the bloodstream, which can lead to dangerously high fevers and precipitous drops in blood pressure.

    Cytokine-release syndrome is a common problem in patients treated with CAR T cells. In the POB and CHOP trials, patients with the most extensive disease prior to receiving the CAR T cells were more likely to experience severe cases of cytokine-release syndrome.

    For most patients, trial investigators have reported, the side effects are mild enough that they can be managed with standard supportive therapies, including steroids.

    The research team at CHOP noticed that patients experiencing severe reactions all had particularly high levels of IL-6, a cytokine that is secreted by T cells and macrophages in response to inflammation. So they turned to two drugs that are approved to treat inflammatory conditions like juvenile arthritis: etanercept (Enbrel®) and tocilizumab (Actemra®), the latter of which blocks IL-6 activity.

    The patients had “excellent responses” to the treatment, Dr. Grupp said. “We believe that [these drugs] will be a major part of toxicity management for these patients.”

    The other two teams subsequently used tocilizumab in several patients. Dr. Brentjens agreed that both drugs could become a useful way to help manage cytokine-release syndrome because, unlike steroids, they don’t appear to affect the infused CAR T cells’ activity or proliferation.

    Improving the Process

    Even with these encouraging preliminary findings, more research is needed before CAR T-cell therapy becomes a routine option for patients with ALL.

    “We need to treat more patients and have longer follow-up to really say what the impact of this therapy is [and] to understand its true performance characteristics,” Dr. Grupp said.

    Several other trials testing CAR T cells in children and adults are ongoing and, with greater interest and involvement from the pharmaceutical and biotechnology sector, more trials testing CAR T cells are being planned.

    Researchers are also studying ways to improve on the positive results obtained to date, including refining the process by which the CAR T cells are produced.

    Research groups like Dr. Brentjens’ are also working to make a superior CAR T cell, including developing a better receptor and identifying better targets.

    For example, Dr. Lee and his colleagues at NCI have developed CAR T cells that target the CD22 antigen, which is also present on most B cells, although in smaller quantities than CD19. The CD22-targeted T cells, he believes, could be used in concert with CD19-targeted T cells as a one-two punch in ALL and other B-cell cancers. NCI researchers hope to begin the first clinical trial testing the CD22-targeted CAR T cells in November 2014.

    Based on the success thus far, several research groups across the country are turning their attention to developing engineered T cells for other cancers, including solid tumors like pancreatic and brain cancers.

    The stage has now been set for greater progress, Dr. Lee believes.

    NCI investigators, for example, “now have a platform to plug and play better CARs into that system, without a lot of additional R&D time,” he continued. “Everything else should now come more rapidly.”

    Updated: October 16, 2014

    http://www.cancer.gov/about-cancer/treatment/research/car-t-cells
  • David
  • 澳洲一女成為世界上第一位同時用賀癌平Herceptin 和 Keytruda 治療的病人



    Australia Recruits World's First Patient to Landmark Breast Cancer Clinical Trial





    Media Release - 28/04/2015







    An Australian woman has become the world’s first patient to be enrolled in an international breast cancer clinical trial, which will be testing the anti-tumour activity of a new drug called KEYTRUDA when combined with trastuzumab.

    KEYTRUDA is part of a class of drugs called immunotherapies, which helps the immune system destroy cancer cells. It has already shown positive results in the treatment of melanoma, lung cancer and other types of cancer. Trastuzumab is currently used in the treatment of HER2 positive breast cancer. However the combined use of these drugs has not yet been tested.

    The PANACEA clinical trial (IBCSG 45-13) is for women diagnosed with advanced HER2 positive breast cancer, which aims to find out the most suitable dose of KEYTRUDA (pembrolizumab, MK-3475) and trastuzumab when these drugs are used together and to assess if their combined use is an effective anti-cancer treatment.

    PANACEA is a global clinical trial which is being coordinated in Australia by the Australia and New Zealand Breast Cancer Trials Group (ANZBCTG). The ANZBCTG is the largest independent oncology clinical trials research group in Australia and New Zealand and for more than 35 years it has conducted a national clinical trial research program for the treatment, prevention and cure of breast cancer. The study is being led by the International Breast Cancer Study Group (IBCSG) under the Breast International Group (BIG) umbrella.

    Associate Professor Sherene Loi from the Peter MacCallum Cancer Centre is the International Study Chair for the PANACEA clinical trial and says the enrolment of the first woman to the study demonstrates the commitment of local researchers to improving treatment options available to women.

    “Australian researchers are committed to high quality clinical trials research, which has led to significant improvements to breast cancer survival rates over the last 20 years. Given the success of KEYTRUDA in the treatment of other cancers, we are hopeful that the PANACEA clinical trial will also benefit women diagnosed with advanced HER2 positive breast cancer.”

    Trastuzumab and KEYTRUDA are monoclonal antibodies. Naturally occurring antibodies are made by the body to protect against infection by attacking foreign substances. A monoclonal antibody is a laboratory-produced antibody that is carefully engineered to mimic the antibodies that are naturally produced as part of the immune system's response to germs, vaccines, and other invaders.

    “KEYTRUDA is a monoclonal antibody that works against a protein called PD-1 found on the surface of immune cells surrounding tumor cells. It is thought that cancer cells produce other proteins, such as PD-L1 and PD-L2, which bind to PD-1 on immune cells and suppress the ability of the immune system to kill cancer cells. The drugs trastuzumab and KEYTRUDA are being tested together to see if they can inhibit the binding of proteins, such as PD-L1 and PD-L2, to PD-1 in breast cancer, thus reactivating the body’s immune system to identify and kill breast tumour cells,” said Associate Professor Loi.

    The ANZBCTG is Australia’s national breast cancer research group dedicated entirely to breast cancer research through the conduct of multi-institution and international clinical trials. The research program involves more than 700 members at over 80 leading medical institutions in Australia and New Zealand. The ANZBCTG’s fundraising department is the Breast Cancer Institute of Australia.

    More information about the PANACEA clinical trial (IBCSG 45-13) can be found at https://clinicaltrials.gov/ct2/show/NCT02129556?term=PANACEA&rank=2. Information about the ANZBCTG and its research program is available at www.anzbctg.org.


    Media contact:
    To arrange an interview with Associate Professor Sherene Loi, please contact –
    Anna Fitzgerald,
    ANZBCTG Communications Manager
    Phone: 02 4925 5255 or 0488 053 659
    Email: anna.fitzgerald@anzbctg.org

    https://www.bcia.org.au/news-stories/245/australia-recruits-world-s-first-patient-to-landmark-breast-cancer-clinical-trial
  • David
  • 我之前讀到的報告 anti pd1治療大腸癌反應率在20%左右
    剛好基因修復缺陷病人發生率為15% 至20%左右
    Merck這份6月在ASCO發表的研究
    確定基因修復(MMR)缺陷 可以用來做 anti pd1治療是否有效的genomic marker

    大腸癌病人如果癌症起因於基因修復(MMR)缺陷
    使用Keytruda 反應率(ORR)高達62% 疾病控制率(DCR)高達92%
    但若是沒有此缺陷 反應率是0% 疾病控制率(DCR)為16%

    48位臨床實驗大腸癌病人 每位都接受過多次化放療 其中13位有基因修復缺陷
    在用Keytruda 治療後 8位腫瘤縮小 反應率為62% 其他25位沒有基因修復缺陷的病人 沒有一位有反應 反應率為0%

    in 48 evaluable, heavily pre-treated patients with advanced colorectal cancer and other solid tumors. In the colorectal cancer group with MMR-deficient tumors, an objective response rate (ORR) of 62 percent was observed (n=8/13). In contrast, no responses were observed in the colorectal cancer group with MMR-proficient tumors (n=0/25).

    醫學的Overall Response Rate (ORR) 我翻譯為反應率 是有嚴謹定義的
    ORR是指腫瘤有縮小的比率 還有一群人有免疫反應 但是因為種種原因
    (像是基因突變數量 見下文) 免疫反應不足以讓腫瘤縮小 但是病人病情穩定
    病情沒有繼續惡化 醫學用 disease control rate (DCR) 來區別

    Keytruda 在有基因修補缺陷的大腸癌病人ORR是62% DCR 是92%
    Keytruda 在沒有基因修補缺陷的大腸癌病人ORR是0% DCR 是16%

    In the group with MMR-deficient colorectal cancer, the ORR was 62 percent and the disease control rate (DCR) was 92 percent. No responses were observed in the colorectal cancer group with MMR-proficient tumors and the DCR was 16 percent.

    ORR 62% DCR 92%是讓人驚喜的數字
    相信是有基因修復(MMR)缺陷的病友的福音
    如果你的醫師太忙還沒注意到這消息
    底下這網頁是ASCO的官網

    ASCO 2015: Mismatch Repair Deficiency Predicts Response to Pembrolizumab Among Patients With Colorectal and Other Cancers

    http://www.ascopost.com/ViewNews.aspx?nid=27670

    我不是在談未來
    anti pd1藥已經有了 MMR缺陷測試是很普遍的測試
    大腸癌病友應該都要測驗一下有沒有MMR缺陷

    MMR 缺陷的病人 平均有1782個突變
    沒有MMR 缺陷的病人平均有73個突變
    越多突變免疫系統越容易辨識癌細胞 免疫反應也越大
    Keytruda 效果也越明顯

    In this study, mismatch repair–deficient tumors had an average of 1,782 mutations, compared to 73 mutations in mismatch repair–proficient tumors. Higher numbers of mutations were linked to better response to pembrolizumab.