Prospects for gene therapy and lymphokine therapy for metastatic melanoma.

Conventional treatment of cancer, especially for patients with metastatic melanoma tumor, is often ineffective. Immunotherapy and recently introduced gene therapy have revolutionized the treatments of patients with metastatic melanoma tumor. Use of biological response modifiers, such as interleukins and interferons, have been found to enhance therapeutic benefits to patients with malignant melanoma. Initial studies with a high-dose interleukin-2 (IL-2) therapy have proved effective in patients with melanoma tumor, although a variety of systemic toxicities were observed. A low-dose IL-2 continuous infusion has shown a similar response in patients with melanoma tumor, but produced lesser toxicity. The low-dose IL-2 therapy has been studied with an adoptive transfer combined with either autologous lymphokine activated killer cells or autologous tumor infiltrating lymphocytes (TIL). IL-2 in combination with chemotherapeutic agents such as flavone acetic acid, dacarbazine, and cyclophosphamide have also been studied in patients with metastatic melanoma. Results have shown a moderate response in patients with metastatic melanoma. TIL therapy, however, has been shown to result in higher objective regression due to potent tumor-specific killing and tumor-specific targeting characters of the TIL. The tumor targeting nature of the TIL creates the possibility of using TIL as a vehicle to deliver gene product specifically to tumor tissue. Safety and toxicity of gene-transduced TIL were addressed by the use of neomycin-resistant, gene-transduced TIL in patients with metastatic melanoma. We also investigated the use of vaccinia oncolysate therapy by using the viral oncolysate prepared with IL-2 gene encoded vaccinia virus. Preliminary studies with murine hepatic metastases colon model have shown encouraging results.     

Durability of complete responses in patients with metastatic cancer treated with high-dose interleukin-2: identification of the antigens mediating response.

OBJECTIVE: To determine the durability of complete responses in patients with metastatic melanoma or renal cancer treated with high-dose bolus interleukin-2 (IL-2) as well as the factors associated with the development of a complete response and the antigens mediating clinical responses. METHODS: A consecutive series of 409 patients with either metastatic melanoma or renal cancer who were treated with high-dose bolus IL-2 in the Surgery Branch, National Cancer Institute, between September 1985 and November 1996 have been analyzed with a median potential follow-up of 7.1 years. All patients were treated with 720,000 IU/kg administered by 15-minute intravenous infusions every 8 hours for up to 5 days as clinically tolerated per cycle. Two cycles constituted a treatment course. Tumor-infiltrating lymphocytes (TIL) from melanoma patients were used to clone the genes encoding the tumor antigens responsible for clinical responsiveness. RESULTS: Thirty-three of 409 (8.1%) patients treated with high-dose bolus IL-2 achieved a complete response and 37 (9%) achieved a partial response. Complete regression was seen in 6.6% and 9.3% of patients with metastatic melanoma and renal cancer, respectively. Twenty-seven of these 33 completely responding patients (82%) remain in ongoing continuous complete response from 39 to more than 148 months from the onset of treatment. Tumor regressions were seen at virtually all organ sites. The absence of prior treatment with immunotherapy, the total dose of IL-2 administered, and the maximal rebound lymphocytosis after cessation of IL-2 correlated with achieving a complete response. Expression cloning techniques have identified a series of tumor antigens that are recognized by TIL grown from resected melanomas. These antigens are mainly melanoma/ melanocyte differentiation antigens, although mutated intracellular proteins can also serve as antigens. CONCLUSIONS: Treatment with high-dose bolus IL-2 mediates complete cancer regression in approximately 8% of patients with metastatic renal cancer and melanoma. The great majority of these patients will enter durable complete regressions and appear to be cured of their metastatic cancer. Thus, immunotherapy with high-dose bolus IL-2 should be considered as initial therapy for appropriately selected patients with metastatic melanoma and renal cell cancer. Identification of the tumor antigens mediating clinical response is opening new therapeutic possibilities for cancer treatment.     

LAK cell adoptive immunotherapy and its problems

Clinical efficacy of lymphokine-activated killer (LAK) cell adoptive immunotherapy (AIT) in combination with plasma exchange and interleukin (IL-2) was investigated in 24 patients with advanced cancer. Partial response (PR) was found in 4 patients (20%), including 1 primary liver tumor, 1 metastatic lung tumor from renal cancer and 2 malignant pleural effusions from gastric and lung cancer. Based on these results new AIT in combination with plasma exchange, OK-432, IL-2 and cyclophosphamide was designed to target liver and lung tumors, in which LAK cells and other drugs were administered through the catheter located in the feeding artery of the tumor. Out of ten patients treated, 1 (10%) with metastatic liver tumor from gallbladder cancer was evaluated as PR. It is suggested that a strategy to enhance tumor accumulation and recognition of LAK cells should be attempted for development of gastrointestinal cancer therapy with AIT.     

Experience with the use of high-dose interleukin-2 in the treatment of 652 cancer patients.

We have administered 1039 courses of high-dose interleukin-2 (IL-2) to 652 cancer patients. Five hundred ninety-six patients had metastatic cancer that either had failed standard effective therapies or had disease for which no standard effective therapy existed, and 56 patients were treated in the absence of evaluable disease in the adjuvant setting. IL-2 was administered either alone (155 patients) or in conjunction with activated immune cells such as lymphokine activated killer (LAK) cells (214 patients) or tumor infiltrating lymphocytes (TIL) (66 patients), with other cytokines such as alpha interferon (a-IFN)(128 patients) or tumor necrosis factor (TNF)(38 patients), with monoclonal antibodies (32 patients), or with the chemotherapeutic agent cyclophosphamide (19 patients). Initial results with the treatment of high-dose IL-2 alone or in conjunction with LAK cells have indicated that objective regressions of cancer can be achieved in 20% to 35% of patients with selected advanced metastatic cancers. Although most responses have been seen in patients with metastatic renal cell cancer, melanoma, colorectal cancer, and non-Hodgkin's lymphoma, many histologic types of cancer have not been treated in significant numbers. These regressions can be durable; of 18 patients achieving a complete response, ten have not experienced recurrence at intervals from 18 to 52 months. Although combinations of IL-2 with TNF do not appear to result in increased responses, there is a suggestion in our initial phase I studies that the combination of a-IFN and IL-2 is more effective than the administration of cytokine alone and this combination deserves further study. Similarly the adoptive transfer of TIL in conjunction with IL-2 also appears to be more effective than the use of IL-2 alone. The toxic side effects in patients treated with high-dose IL-2 are presented and include malaise, nausea and vomiting, hypotension, fluid retention, and organ dysfunction. Treatment-related deaths were seen in 1% of all treatment courses and in 1.5% of patients. These studies demonstrate that a purely immunologic manipulation can mediate the regression of advanced cancers in selected patients and may provide a base for the development of practical, effective biologic treatments for some cancer patients.     

Prospects for cellular immunotherapy for metastatic melanoma.

Systemic therapy for metastatic malignant melanoma has been disappointing. The search for alternate therapeutic methods includes investigation of the interaction between melanoma and the human immune system. A cellular immune response to melanoma has been documented in vitro and in vivo. In most patients with disseminated disease, however, immune T cells fail to eradicate the tumor. While this phenomenon is poorly understood, the occasional occurrence of spontaneous regression provides some indication that the immune response may, in fact, be capable of eradicating established tumor in vivo. Current efforts to augment and to direct the immune response to melanoma include investigation of specific and nonspecific adoptive immunotherapy. Specific therapy includes the generation of tumor-activated specific killer cells from peripheral blood, draining nodes, or metastatic tumor deposits. An increasing understanding of antigen recognition and improved methodology for T-cell culture are contributing toward the application of cellular immunotherapy to patients with melanoma.     

The development of new immunotherapies for the treatment of cancer using interleukin-2. A review.

Recent increases in knowledge of cellular immunology, combined with developments in biotechnology, have provided new opportunities for the development of immunotherapies for the treatment of cancer in humans. One approach to therapy is that of adoptive immunotherapy, that is, the transfer to the tumor bearing host of lymphoid cells with antitumor reactivity that can mediate antitumor responses. Several lymphocyte subpopulations have now been identified that may be suitable for use in adoptive immunotherapy. Resting lymphocytes incubated in interleukin-2 (IL-2) give rise to lymphokine activated killer (LAK) cells that can lyse malignant cells, but not normal cells. Clinical studies in patients with advanced cancer have revealed that treatment with high dose IL-2 alone or in combination with LAK cells can mediate the complete or partial regression of cancer in selected patients. Other approaches are currently undergoing investigation, including the adoptive transfer of tumor infiltrating lymphocytes, which, in animal models, have antitumor reactivity 50-100 times more potent than do LAK cells. Other new approaches to immunotherapy include the use of combination of lymphokines, such as the use of tumor necrosis factor or alpha interferon in conjunction with IL-2. The availability of recombinant lymphokines that provide large amounts of biologically active materials can hopefully lead to the development of effective new therapies for cancer in humans.     

Adoptive Immunotherapy of Patients with Metastatic Renal Cell Cancer Using Lymphokine-Activated Killer Cells, lnterleukin-2 and Cyclophosphamide: Long-Term Results

Background Initial results of adoptive immunotherapy using lymphokine-activated killer (LAK) cells and interleukin-2 (IL-2) appeared to offer promise for treating renal cell cancer (RCC). However, lower response rates were seen in subsequent trials, and the long-term results of this treatment method have not been fully reported. In this study, we examine long-term results of adoptive immunotherapy using LAK cells, IL-2, and cyclophosphamide (LAK/IL-2/CPM therapy). Methods We administered 10 courses of therapy to 9 patients with advanced RCC. One patient had liver and para-aortic lymph node metastases; the others had only lung metastases. The clinical effects were initially evaluated 4 weeks after therapy and follow-up was continued for periods of 43 to 76 months. Results The 4-week evaluation revealed 3 complete responses (CR), 3 partial responses (PR), 1 minor response (MR), 1 patient with no change in disease status (NC), and 2 patients whose disease progressed (PD). One CR patient remained apparently free of disease for 43 months. After tumors recurred in the lung of another CR patient further disease progression was suppressed by IL-2 administration until the patient died from other causes at 46 months. The third CR patient showed tumor recurrence in the lung and was re-treated with the sameLAK/CPM/IL-2 therapy. Lung tumors decreased in size (PR), but the patient died due to brain metastasis 2 months after the second round of treatment. The 2 initial PR patients, as well as the MR and NC patients, developed regrowth or new metastatic lesions within 2 to 15 months following therapy. The 2 PD patients died 2 and 9 months after therapy. Conclusion Long-term effects ofLAK/IL-2/CPM therapy were not correlated with the maximal response observed 4 weeks after therapy. AlthoughLAK/IL-2/CPM therapy appears suitable for use as induction therapy in RCC, our data suggest that long-term suppression will require surgical removal of remnant tumors or more intensive maintenance therapy.     

Evaluation of a preclinical model of bone metastasis for the study of adoptive immunotherapy

The development of new therapeutic strategies for the treatment of bone metastases strongly depends on the availability of valid animal models. In this paper, we evaluate a preclinical model of bone metastases using a technique of tumor cell injection into the left heart ventricle of mice to study the efficacy of adoptive immunotherapy. Using flow cytometric analysis and histopathological and radiological examination, we investigated whether this experimental model of bony metastases using two murine cell lines of melanoma and breast cancer would be suitable for the study of adoptive immunotherapy for these diseases. We further report that anti-CD3-activated and IL-2-expanded tumor vaccine draining lymph node cells cause regression of tumor metastases, including bone metastases, following adoptive transfer to mice bearing 3-day metastases from the D5 melanoma cell line. These promising early results lead us to conclude the following: (1). this model of experimental bone metastases is suitable for the study of immunotherapy, and (2). further studies are warranted to extend these promising early findings of the therapeutic effects of adoptive immunotherapy in this animal model.     

Advanced renal cell carcinoma treated with granulocyte-macrophage colony-stimulating factor gene therapy: A clinical course of the first Japanese experience

A phase I study of granulocyte-macrophage colony-stimulating factor (GM-CSF) gene-transduced tumor vaccine for patients with metastatic renal cell carcinoma (RCC) was initiated in 1998, as the first cancer gene therapy in Japan. The study is still ongoing, but the first patient is presented here as a case report. The patient was a 60-year-old man with Stage IV CRC with multiple lung metastases. After surgical resection of the tumor, autologous tumor cells were transduced and cultured to produce GM-CSF. The patient received a total of 2.2 x 108 gene-transduced autologous vaccine cells by subcutaneous injection. During the course of vaccination, growth of the largest metastatic mass slowed to some extent; however, multiple new lesions developed. About 1 month after the start of low-dose IL-2 therapy, rapid and remarkable regression in a large lung hilar metastatic mass was noticed. The patient died of progressive disease 7 months after the start of GM-CSF gene therapy. Careful histological examination by autopsy revealed that the responding mass was infiltrated by CD8 positive dominant T lymphocytes, and did not exhibit vasculitis or any other changes associated with active autoimmune disease.     

Interleukin-12 immunotherapy of murine transitional cell carcinoma of the bladder: dose dependent tumor eradication and generation of protective immunity

PURPOSE: The antitumor activity of interleukin (IL)-12 has been demonstrated in a number of tumor models but barely tested in bladder cancer models. We evaluated the antibladder cancer activity of this cytokine in syngeneic mice bearing subcutaneous, metastatic and orthotopic tumors. MATERIALS AND METHODS: Mice were implanted subcutaneously, intravenously or orthotopically with syngeneic transitional cell carcinoma (TCC) of the bladder. The tumor bearing mice were then treated with IL-12 locally or systemically and monitored for tumor regression and survival. RESULTS: In the subcutaneous model dose dependent suppression of tumorigenesis was observed when IL-12 was administered subcutaneously at a distal site with the MB49 line being more sensitive than MBT-2. IL-12 (10 days) above 50 ng daily was tumor inhibitory, while doses of 500 or 1000 ng daily prolonged survival and cured 70% and 75% of subjects, respectively. Upon re-challenge with parental tumor cells mice previously cured with IL-12 (1000 vs 500 ng daily) exhibited specific protection (70% vs 35% rejection) that was dependent on the earlier dose of cytokine. IL-12 administered intraperitoneally at a dose of 250 ng daily was more potent than subcutaneous administration and complete regression was observed. Metastatic TCC in the lungs and orthotopic tumors in the bladder also favorably responded to systemic or intravesical IL-12 therapy, respectively. Addition of IL-2 to IL-12 therapy increased tumor regression, long-term survival and rejection of re-challenged parental tumor. CONCLUSIONS: IL-12 is exceptionally effective for treating murine bladder TCC in subcutaneous, metastatic and orthotopic models. The antibladder cancer activity of this cytokine should be tested in human bladder cancer therapy.     

Successful adoptive immunotherapy of metastatic renal cell carcinoma with in vitro immunized autologous lymphocytes and cimetidine

Summary We report the results from a clinical trial of adoptive immunotherapy conducted in 20 patients with metastatic renal cell carcinoma, a form of cancer unresponsive to traditional modalities of treatment. This novel approach is based on our previously described method for in vitro primary immunization of human peripheral blood mononuclear cells (PBM). Patient PBM were depleted of suppressor T-cells and immunized in vitro against an autologous tumor antigen extract in the presence of a non-specific lymphocyte activator. After 1 week in culture the in vitro immunized cells were infused back into the patient. Each patient received a total of three infusions, delivered at weekly intervals of 50–150×106 cells per infusion. In addition, patients were treated with oral cimetidine, 600 mg 4×/day, as an anti-suppressor cell agent. A total of 60 immunized cell infusions were given to the 20 patients and no serious technical problems were encountered with this therapy. In addition, after follow-up of longer than 2 years in individual patients, we can report that toxicity is minimal, consisting only of four brief episodes of low-grade fever following infusion of the immunized cells. Of the 20 patients treated, 14 are evaluable with regard to therapeutic efficacy. Of these 14 patients, 9 (64%) had an objective response to this therapy. Three patients had a partial response (decrease of >50% of tumor), sustained for 18 months in two patients and still on-going in one of them. Two patients had tumor regression (decrease of >25% but <50% of tumor), and four patients have remained clinically stable for several months, after previously demonstrating rapid metastatic growth. This report corroborates previous observations concerning the usefulness of adoptive immunotherapy in cancer, but represents a significant improvement with regard to the use of specifically immunized lymphocytes and the addition of anti-suppressor cell therapy. Although many questions remain, we believe that expanded clinical studies using this treatment approach are justified at this time.     

Surgical resection for metastatic melanoma to the lung

From 1971 through December 1986, the courses of 47 patients who underwent thoracotomy for pulmonary metastases from melanoma were retrospectively reviewed to determine the efficacy of this approach in the management of selected patients with melanoma. The overall five-year survival rate was 25% (median survival, 19 months). Thirty-eight patients were free of disease following thoracotomy. These patients fared significantly better than those who had residual disease following thoracotomy, with a five-year survival rate of 31% (median survival, 24 months) compared with 0% (median survival, six months). Survival was not influenced by the addition of adjuvant therapy or duration of time before the development of metastases (less than 12 months vs greater than or equal to 12 months). In selected patients with melanoma metastatic to the lung, thoracotomy with complete excision of the metastatic deposits results in improved survival and should be considered the treatment of choice.     

重组腺病毒介导IL-12、IL-2联合基因治疗前列腺癌的实验研究

目的　探讨转移性前列腺癌的治疗方法 ,为前列腺癌免疫基因治疗提供实验依据。　方法　采用重组腺病毒介导IL 12、IL 2联合免疫基因疗法 ,对 6 6只C5 7BL/ 6小鼠前列腺癌模型进行致瘤性和抑瘤性观察。　结果　腺病毒AdmIL 12、AdhIL 2能有效表达目的基因。接种野生型 ,转AdLacZ及转AdmIL 12、AdhIL 2混合RM 1细胞的小鼠致瘤比例分别为 10 / 10、10 / 10及 2 / 10 ;成瘤时间分别为 (12 .3± 1.5 )d、(12 .8± 1.0 )d、(2 2 .5± 2 .1)d ;接种 30d后肿瘤结节直径分别为 (35 .0±2 .0 )mm、(34 .0± 2 .6 )mm、(10 .5± 3.5 )mm。与对照组相比 ,转AdmIL 12、AdhIL 2基因RM 1细胞小鼠致瘤率下降 ,成瘤时间延迟 (P <0 .0 1)、瘤结节小 (P <0 .0 1)。AdmIL 12、AdhIL 2瘤体注射还可抑制肿瘤生长 (P <0 .0 1) ,减少肺转移灶数目 (P <0 .0 1)。　结论　IL 12、IL 2联合基因治疗可诱发前列腺癌小鼠的肿瘤特异性免疫反应。     

Initial Clinical Response Predicts Outcome and Is Associated With Dose Schedule in Metastatic Melanoma and Renal Cell Carcinoma Patients Treated With High-Dose Interleukin 2

Background High-dose interleukin (IL)-2 is an effective agent for the treatment of metastatic malignant melanoma and renal cell carcinoma. This study evaluated the outcomes of patients receiving two commonly used intravenous IL-2 schedules that have never been directly compared.Methods Forty-seven metastatic malignant melanoma and renal cell carcinoma patients were identified from a prospective database who underwent high-dose IL-2 therapy (720,000 or 600,000 IU/kg) during 1999 to 2003. Disease-specific survival (DSS) was calculated by the Kaplan-Meier method with the log-rank test on an intention-to-treat basis. Multivariate Cox regression analysis of prognostic variables associated with outcome was performed. Factors associated with initial response and prevention of disease progression were determined.Results Objective response (5 partial and 5 mixed) or disease stabilization was noted in 9 (20%) and 10 (22%), respectively, of 46 assessable patients after 1 course of therapy. Four patients (22%) achieved disease-free status after the third course of IL-2 (n = 1) or surgical resection of confined metastatic disease (n = 3). At 19.1 months median follow-up, factors associated with improved DSS included an initial clinical response to IL-2 therapy (P < .001) and a higher administered dose (P = .04). Patients who received 720,000 IU/kg were more likely to experience an initial major objective response (P = .03) and disease stabilization (P = 0.03) independent of the tumor treated. Objective response early in the course of therapy was the only independent predictor of tumor-related mortality (P = .004).Conclusions The initial clinical response to IL-2 therapy is an independent predictor of improved outcome associated with DSS and the 720,000 IU/kg dose. These results support further prospective trials with increased IL-2 dose schedules in a larger cohort of patients.Published by Springer Science+Business Media, Inc. © 2005 The Society of Surgical Oncology, Inc.     

Anti-tumor reactivity of human lymphokine activated killer (LAK) cells against fresh and cultured preparations of renal cell cancer

Immunotherapy utilizing the adoptive transfer of lymphokine activated killer (LAK) cells in conjunction with recombinant interleukin-2 (IL-2) is capable of mediating the regression of established cancer in a variety of animal tumor models as well as advanced metastatic cancers in humans. We have thus examined the variability of the anti-tumor lytic reactivity of LAK cells obtained from patients with metastatic renal cell cancer (RCC). Tumor cell suspensions were prepared by enzymatic digestion from 37 consecutive renal cell tumors. The mean (+/- SEM) total number of cells recovered was 1.5 +/- 2.2 X 10(9) cells per tumor. The percentage of tumor cells in the suspension was 39.1 +/- 3.3% (range: 6 to 75%). Thirteen of 13 different fresh renal tumor cell preparations tested in 57 experiments and tow of two renal tumor lines tested in 10 experiments were all lysed by LAK cells. RCC patients, like normal donors, generated good LAK effectors with broad antitumor activity against autologous as well as allogenic tumors. Both renal and nonrenal tumors were equally lysed by LAK cells. LAK killing of the erythroleukemic tumor lines K562 and Daudi was significantly better than the lysis of fresh autologous and allogeneic tumor targets or cultured RCC tumor lines. Short term tumor cultures derived from renal cancer preparations proved to be sensitive and reliable tumor targets for studying the in vitro killing by LAK cells. Clinical trials testing the therapeutic role of LAK cells and IL-2 in patients with advanced renal cell cancer are currently in progress.     

Hematoporphyrin-derivative and photoradiation therapy of malignant tumors

Kodak projectors with #2418 red Corning filters were used as a light source to treat cutaneous and subcutaneous malignancies in five patients who previously had been given hematoporphyrin derivative (HpD). An argon dye laser system was used to treat malignancies in patients who also were given the HpD. These tumors included 11 melanomas of the eye, three carcinomas of the esophagus, one melanoma of the esophagus, four carcinomas of the lung, three basal cell skin cancers, and one retropharyngeal metastatic oral cancer. Clinical results and technical problems of this therapy are discussed.     

Management of metastatic malignant melanoma of the bladder

Recombinant interleukin-2 (IL-2) has demonstrated antitumor activity and durable clinical responses in patients with metastatic melanoma. Careful screening and selection of appropriate patients has improved the safety profile of IL-2 administration. Gross hematuria would ordinarily preclude the safe delivery of IL-2. We report a case of metastatic melanoma to the bladder presenting with hematuria. A complete resection was performed and subsequently allowed the administration of high-dose, bolus IL-2. The combination of resection and IL-2 therapy resulted in a partial response maintained for more than 18 months. Symptomatic bladder melanoma should be aggressively treated to allow for systemic immunotherapy, which can provide durable responses.     

Preoperative evaluation of pancreatic adenocarcinoma

The preoperative evaluation of resectability for pancreatic cancer fails to identify up to 25% of patients who are unfortunately found to be unresectable at surgical exploration. Inoperative findings in this circumstance is usually due to either small volume metastatic disease or regional tumor invasion. While advances in computed tomography (CT) technology has increased accuracy of local tumor extent, occult metastatic disease remains a common problem. Although 2-[(18)F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) has been demonstrated to be useful in the staging of many malignancies (e.g. esophageal cancer, recurrent colorectal cancer, lung cancer), it has not been found to significantly increase the accuracy of determining resectability preoperatively in pancreatic cancer, especially with regard to detection of small volume metastatic disease. There are a variety of pancreatic cancer-specific antigens which are being developed as a method for targeted molecular imaging; we provide preliminary data targeting the integrin alpha(v)beta(6) to demonstrate the potential feasibility of this approach. Further developments may allow the accurate determination of patients with resectable pancreatic cancer, and more importantly, those with unresectable disease that may forego unnecessary surgery, the associated morbidity, and the subsequent delay of appropriate therapy.     

State of affairs regarding targeted pharmacological therapy of cancers metastasized to the brain

In 1999 a visionary short article by The Wall Street Journal writers Robert Langreth and Michael Waldholz popularized the new term “personalized medicine,” that is to say, the targeting of drugs to each unique genetic profile. From today’s perspective, targeted approaches have clearly found the widest use in the antineoplastic domain. The current review was initiated to review the progress that has been made regarding the treatment of patients with advanced cancer and brain metastases. PubMed was searched for the terms brain metastasis, brain metastases, or metastatic brain in the Title/Abstract. Selection was limited to randomized controlled trial (RCT) and publication date January 2010 to February 2022. Following visual review, 51 papers on metastatic lung cancer, 12 on metastatic breast cancer, and 9 on malignant melanoma were retained and underwent full analysis. Information was extracted from the papers giving specific numbers for intracranial response rate and/or overall survival. Since most pharmacological trials on advanced cancers excluded patients with brain metastases and since hardly any information on adjuvant radiotherapy and radiosurgery is available from the pharmacological trials, precise assessment of the effect of targeted medication for the subgroups with brain metastases is difficult. Some quantitative information regarding the success of targeted pharmacological therapy is only available for patients with breast and lung cancer and melanoma. Overall, targeted approaches approximately doubled the lifespan in the subgroups of brain metastases from tumors with targetable surface receptors such as anaplastic lymphoma kinase (ALK) fusion receptor in non-small cell lung cancer or human epidermal growth factor receptor 2 (HER2)–positive breast cancer. For these types, overall survival in the situation of brain metastases is now more than a year. For receptor-negative lung cancer and melanoma, introduction of immune checkpoint blockers brought a substantial advance, although overall survival for melanoma metastasized to the brain appears to remain in the range of 6 to 9 months. The outlook for small cell lung cancer metastasized to the brain apparently remains poor. The introduction of targeted therapy roughly doubled survival times of advanced cancers including those metastasized to the brain, but so far, targeted therapy does not differ essentially from chemotherapy, therefore also facing tumors developing escape mechanisms. With the improved perspective of patients suffering from brain metastases, it becomes important to further optimize treatment of this specific patient group within the framework of randomized trials.

     

Regional immunotherapy of metastatic renal cell carcinoma

We summarized the current literature concerning regional immunotherapy of pulmonary metastases in metastatic renal cell carcinoma and other malignancies using inhaled interleukin-2 (IL-2). Inhaled IL-2 therapy is associated with minimal toxicity and is effective in preventing progression in metastatic renal cell carcinoma, melanoma, and possibly other diseases such as breast cancer. Local (physiologic) use and systemic (pharmacologic) use of IL-2 are not mutually exclusive; a combination may be very appropriate in metastatic cancer. Local physiologic therapy intensifies treatment without intensifying toxicity.