Immunotherapy of malignant ascites with trifunctional antibodies

A new class of intact bispecific antibodies shows unmet effector qualities by activation of not only T cells but also simultaneous activation of Fcgamma receptor type I/III+ cells (macrophages, NK-cells and DC). These trifunctional antibodies (trAb) lead to efficient specific killing of targeted tumor cells without any pre- or co-stimulation. This concept was investigated in vivo in patients with malignant ascites in a clinical situation that allowed monitoring of tumor cell elimination and correlation with clinical effects. In a prospective study, 8 patients with malignant ascites due to peritoneal carcinomatosis were treated with intraperitoneal application of trAb, which bound either the EpCAM- or Her2/neu-antigen on tumor cells. Treatment consisted of 4-6 applications within 9-23 days with a total amount of 145-940 microg. Seven of eight patients required no further paracentesis during follow-up or until death with a mean paracentesis-free interval of 38 weeks (median = 21.5, range = 4-136). Tumor cell monitoring showed a complete elimination of tumor cells in ascites already at total doses as low as 40-140 microg. Clinical response with disappearance of ascites accumulation was seen in all patients, which was correlated with elimination of tumor cells (p = 0.0014). Severe adverse events were not observed. Clinically relevant side effects were fever, moderate abdominal pain and skin reactions. Intraperitoneal immunotherapy with trAb showed convincing efficacy in patients with malignant ascites. This treatment offers new therapeutic options for patients with peritoneal carcinomatosis.     

Systemic therapy of malignant melanoma

The present status of medical treatment of malignant melanoma is briefly reviewed, both with regard to adjuvant therapy for individuals with high-risk melanoma and a high probability of harbouring subclinical rnicrometastases, as well as to therapy for establised disseminated (macrometastatic) disease. At present, disseminated, macrometastatic melanoma is incurable in the majority of cases. Single agent chemotherapy has modest effects and results in disease remission in a minority of patients, usually of short duration, Combination chemotherapy, or the combination of chemotherapeutic drugs and cytokines, results in increased response rates and occasionally remissions of prolonged duration. So far, no regimen has demonstrated improved survival compared to single agent therapy in disseminated melanoma. New insights into the mechanisms of resistance to chemotherapeutic drugs may lead to development of predictive tests that can identify individuals with tumors sensitive to a specific agent, as well as to the development of strategies to circumvent drug resistance. It has recently been shown that adjuvant therapy of high-risk melanoma with large doses of interferon-α2b significantly prolongs relapse-free and overall survival, at the price of considerable toxicity. Ongoing studies aim to define the optimum dose and duration of adjuvant interferon therapy. Recent advances in molecular biology and immunology may lead to the development of new treatment modalities, such as improved vaccines and other biologic therapies, which may benefit patients with malignant melanoma.     

Characterisation of the new EpCAM-specific antibody HO-3: implications for trifunctional antibody immunotherapy of cancer

Epithelial cell adhesion molecule EpCAM is a transmembrane glycoprotein that is frequently overexpressed in a variety of carcinomas. This pan-carcinoma antigen has served as the target for a plethora of immunotherapies. Innovative therapeutic approaches include the use of trifunctional antibodies (trAbs) that recruit and activate different types of immune effector cells at the tumour site. The trAb catumaxomab has dual specificity for EpCAM and CD3. In patients with malignant ascites, catumaxomab significantly increased the paracentesis-free interval, corroborating the high efficacy of this therapeutic antibody. Here, we characterised the monoclonal antibody (mAb) HO-3, that is, the EpCAM-binding arm of catumaxomab. Peptide mapping indicated that HO-3 recognises a discontinuous epitope, having three binding sites in the extracellular region of EpCAM. Studies with glycosylation-deficient mutants showed that mAb HO-3 recognised EpCAM independently of its glycosylation status. High-affinity binding was not only detected for mAb HO-3, but also for the monovalent EpCAM-binding arm of catumaxomab with an excellent K(D) of 5.6 x 10(-10) M. Furthermore, trAb catumaxomab was at least a 1000-fold more effective in eliciting the eradication of tumour cells by effector peripheral blood mononuclear cells compared with mAb HO-3. These findings suggest the great therapeutic potential of trAbs and clearly speak in favour of EpCAM-directed cancer immunotherapies.     

Adjuvant therapy for malignant melanoma

Malignant melanoma is increasing in incidence worldwide, and many patients remain at a significant risk of recurrence following surgical resection. Over the past 30 years, interferon-α has been the only agent approved for adjuvant therapy of melanoma. This review summarizes the rationale for adjuvant therapy, and discusses the roles of interferon, immunotherapy, chemotherapy and radiation therapy in the adjuvant setting. New approaches and novel combinations that appear promising for the adjuvant therapy of malignant melanoma are also outlined.     

Bronchial malignant melanoma

We describe a case of malignant melanoma presenting initially as an endobronchial lesion located in the left main bronchus causing total atelectasis. This resolved with radiation therapy. Widespread metastases developed shortly thereafter. The differential diagnosis of primary and metastatic bronchial malignant melanoma is discussed. Other isolated case reports are reviewed.     

无色素性恶性黑色素瘤28例诊断及治疗分析

目的分析无色素性恶性黑色素瘤的诊断及治疗的结果.方法1986年3月至2000年10月,我们收治了28例无色素性恶性黑色素瘤患者,全部经免疫组化确定.结果1年生存率71%,2年生存率39%,3年生存率25%,5年生存率7%,最长生存6年.结论无色素性恶性黑色素瘤,很容易误诊为其它恶性肿瘤,需做免疫组化才能确诊,合理的将手术、化疗、单次大剂量放疗及免疫治疗结合起来,是目前治疗恶性黑色素瘤的主要方法.     

Thermoradiotherapy of malignant melanoma

From 1978 through February 1986, 49 measurable lesions in 18 patients with recurrent primary or metastatic malignant melanomas were treated with a combination of radiation therapy and hyperthermia. The primary sites were head and neck (eight), chest wall (two), pelvis (one), upper extremities (three), and lower extremities (35). Because of the length of the study, the dose and fractionation of radiation therapy varied (dose per fraction from less than 400 cGy to 800 cGy and a total dose of 2000 cGy to 6000 cGy). This variation was mostly dependent on the prior course of radiation therapy of these lesions. The hyperthermia technique used in these patients was superficial local microwave hyperthermia; a minority of patients were treated with ultrasound. Complete response was achieved in 29 lesions (59–2 per cent) and partial response in six lesions (12 per cent). In a separate analysis of 67 lesions with superficial malignant melanoma who were treated by radiation therapy alone, a 24 per cent complete response and a 34 per cent partial response were achieved. Detailed analyses are presented in regard to dose per fraction, total radiation dose, and the size of lesions.     

Inflammatory demyelinating polyneuropathy: A complication of immunotherapy in malignant melanoma

Paraneoplastic syndromes (PNS) involving the central nervous system are arare manifestation of malignant disease. As they commonly precede thediagnosis of malignancy their acute manifestations do not often presentthemselves to oncologists in the first instance. It is currently believed thatmost, if not all, neurological PNS are autoimmune in nature. Proteinsexpressed ectopically on the surface of tumour cells generate an immuneresponse which cross-reacts with the same, or similar, proteins in the nervoussystem resulting in damage. This can involve a single cell type of the nervoussystem whilst in other cases the impairment is more widespread.The following report is of a case of chronic inflammatory demyelinatingpolyneuropathy (CIDP) occurring in metastatic malignant melanoma, followingtreatment with interferon-. We review the current literature on this rareassociation and speculate on its pathogenesis, and the implications for futuretherapeutic strategies in melanoma targeting tumour antigens.     

Effects of intralymphatic immunotherapy on natural killer activity in malignant melanoma patients

Adjuvant immunotherapy has the theoretical attraction of augmenting the host immune response at a time when the tumor burden is low. We have previously reported that intralymphatic immunotherapy (ILI) augments the cytolytic humoral immune responses in melanoma patients. This study was undertaken to assess the effects of ILI on cell-mediated immunity. As a model for the cellular effects of ILI, we investigated the natural killer (NK) cell activity in malignant melanoma patients. Fourteen patients were given an allogeneic cultured tumor cell vaccine (TCV) intralymphatically with concomitant administration of BCG. Natural killer cell activity was assessed sequentially using the single cell lysis and binding assay. Overall NK activity against the K562 target cell line showed a moderate increase over pretreatment levels as reflected by the increased number of target binding lymphocytes. However, the percentage of target binders mediating cell lysis remained unchanged during treatment. Assessment of NK activity against the NK-resistant M14 melanoma cell line reflected similar findings. These results suggest the activation of NK cells by tumor antigens, BCG, and/or alloimmunization with TCV. This increase appears to be manifested by increased target recognition rather than by alterations in effector cell function.     

Improved therapeutic efficacy of unmodified anti-tumor antibodies by immune checkpoint blockade and kinase targeted therapy in mouse models of melanoma

The use of specific anti-tumor antibodies has transformed the solid cancer therapeutics landscape with the relative successes of therapies such as anti-HER2 in breast cancer, and anti-EGFR in HNSCC and colorectal cancer. However, these therapies result in toxicity and the emergence of resistant tumors. Here, we showed that removing immune suppression and enhancing stimulatory signals increased the anti-tumor activity of unmodified TA99 antibodies (anti-TYRP1) with a significant reduction of growth of solid tumors and lung metastases in mouse models of melanoma. Immune checkpoint blockade enhanced the efficacy of TA99, which was associated with greater CD8⁺/Foxp3⁺, NK1.1⁺ and dendritic cell infiltrates, suggestive of an increased anti-tumor innate and adaptive immune responses. Further, MEK inhibition in melanoma cell lines increased the expression of melanosomal antigens in vitro, and combining TA99 and MEKi in vivo resulted in enhanced tumor control. Moreover, we found an improved therapeutic effect when YUMM tumor-bearing mice were treated with TA99 combined with MEKi and immune checkpoint blockade (anti-PD1 and anti-CTLA4). Our findings suggest that MEKi induced an increased expression of tumor-associated antigens, which in combination with anti-tumor antibodies, generated a robust adaptive anti-tumor response that was sustained by immune checkpoint inhibition therapy. We postulate that combining anti-tumor antibodies with standard-of-care strategies such as immune checkpoint blockade or targeted therapy, will improve therapeutic outcomes in cancer.     

皮肤恶性黑色素瘤患者预后的影响因素分析

目的分析皮肤恶性黑色素瘤(MM)患者预后的影响因素。方法选取74例接受手术联合免疫治疗的皮肤MM患者,采用Cox比例风险回归模型分析影响皮肤MM患者预后的危险因素。结果 74例皮肤MM患者中,死亡33例。单因素分析结果显示,不同TNM分期、肿瘤破溃情况、淋巴结转移情况、Clark分级皮肤MM患者的2年生存率比较,差异均有统计学意义(P<0.05);不同病理类型皮肤MM患者的2年生存率比较,差异无统计学意义(P>0.05)。Cox比例风险回归模型分析结果显示,TNM分期为Ⅲ～Ⅳ期、有淋巴结转移、有肿瘤破溃、Clark分级为Ⅲ～Ⅴ级是影响手术联合免疫治疗后皮肤MM患者预后的独立危险因素(P<0.01)。结论手术联合免疫治疗对皮肤MM具有较好的效果,临床上应重视患者的TNM分期、淋巴结转移情况、肿瘤破溃情况和Clark分级对皮肤MM患者预后的影响。     

Late recurrence of stage I malignant melanoma

Although the introduction of well-established risk factors has made the clinical course and prognosis of malignant melanoma disease much more predictable, in a considerable number of patients the disease's course is still not as expected. One group to which this applies are stage I melanoma patients who develop metastatic disease after 10 years or more of a disease-free interval. In our series of 94 such patients, 6 developed late relapse of their disease. The subsequent survival of these patients did not relate to any of the primary tumors' characteristics, but to the pattern of the late recurrence. Four patients with visceral metastases were dead within 1 to 5 years following relapse, one patient with lymph node involvement is alive with metastases, and another patient with skin metastases has no signs of disease following surgery and immunotherapy. Our conclusion is that malignant melanoma patients should be placed under close follow-up for the rest of their lives.     

Blood groups and malignant melanoma

The charts of 168 patients with malignant melanoma were reviewed with regard to the incidence of the major blood groups. Blood group A was encountered in 39.9%, Group B in 7.7%, Group AB in 3%, and Group O in 49.4%. Although blood group O had a higher frequency compared to that of the general white population of various series, the difference was not significant. Patients with blood group A had a median survival of 67.7 months whereas patients with blood group O had a median survival of 46.6 months (p = 0.04). The improved survival for blood group A remained significant only in female patients, when the sexes were considered separately. However, group A had an incidence of 24% in early Clark's lesions while that incidence in group O was 9.8%. Female patients had longer median survival (86 months) than male patients (44 months).     

Psychosocial support and malignant melanoma

The holistic care of patients with malignant melanoma requires psychosocial intervention. This paper provides an argument in support of this, based on research findings, clinical experience, demand and implications for the future. Strategies for providing psychosocial support are outlined with emphasis on a coordinated multidisciplinary approach, specialist nursing contributions and self-help. Recent innovations are described with recommendations for similar strategies to be employed in the prevention of disease and associated morbidity.     

Primary malignant melanoma of the esophagus

A 48-year-old woman presented with a 6-month history of dysphagia, often associated with retrosternal chest pain. Upper endoscopy revealed an unusual pigmented lesion within the middle portion of the esophagus, and multiple biopsies were obtained. The histopathology and immunohistochemical profile of the tissue specimens were diagnostic of malignant melanoma. A thorough clinical and radiographic evaluation was performed, providing no additional findings or alternative primary source. Of approximately 11,500 melanoma patients entered in the Duke University melanoma database since 1970, this represents the only case of primary esophageal melanoma. The case is described and a review of the literature is presented. J. Surg. Oncol. 1997;66:201–206. © 1997 Wiley-Liss, Inc.     

原发性食管恶性黑色素瘤临床病理特征及组织发生

目的　讨论原发性食管恶性黑色素瘤的诊断、鉴别诊断、组织发生和生物学行为。方法　报道 2例原发性食管恶性黑色素瘤并进行临床表现、组织形态学和免疫组织化学的观察研究 ,结合文献对其诊断、鉴别诊断和组织来源进行探讨。结果　原发性食管恶性黑色素瘤好发于中老年 ,临床症状多为进行性吞咽困难 ,肿瘤多位于食管中下段 ,大体形态多呈息肉状 ,Fontana组织化学染色瘤细胞显示出嗜银性黑色素颗粒 ;免疫组化染色瘤细胞S 10 0和HMB45均为阳性。结论　食管中下段息肉样肿物在中老年患者应想到原发性食管恶性黑色素瘤的可能 ,最后确诊特别是无色素性恶黑需要靠免疫组织化学标记或电镜的支持。该肿瘤的组织发生可能来自食管粘膜基底层的黑色素细胞。     

Neoadjuvant therapy for melanoma: A critical appraisal

The treatment of advanced melanoma has significantly changed since the development of targeted and immune therapy. To date, these agents have primarily been used in the adjuvant or metastatic setting. Given several theoretical advantages, there is increased interest in the use of these new therapeutics in the neoadjuvant setting. In this review, we detail the potential benefits and pitfalls of neoadjuvant therapy for melanoma, review the currently available data, and describe ongoing neoadjuvant trials.     

Major amputation for malignant melanoma: An epidemiological study

The annual number of amputations in Denmark as a consequence of malignant melanoma on the limbs has been constant during the period 1978–1987. In contrast, the number of malignant melanoma localized to the extremities increases. For lower limb amputation the mean age is 58 y for males and for females, 72 y. The sex ratio, male to female is 1:2.2. Of the 13 male amputees 7 (54%) had died after 18 mo, of the 28 female amputees 20 (74%) had died after 19 mo. An analysis (Kaplan-Meier) shows a 5-y survival rate of about 28%. The mortality is found to be related to sex and level of amputation. Six cases of upper extremity amputation are presented. A review of the literature in order to compare the demographic factors and to outline the indications for amputation reveals a number of differences, most significantly the higher mean age at time of amputation (about 65 y) in Denmark than the figures earlier published (about 45 y). The consensus seems to be that amputation is rarely indicated except as a form of palliation. © 1993 Wiley-Liss, Inc.