Hazards and complications of BCG immunotherapy.

The hazards and complications of BCG immunotherapy, as well as the potential for enhanced tumor growth, make it imperative that the clinician know the clinical setting in which BCG can offer therapeutic benefit. This would include the intratumor injection of localized intradermal tumor deposits of melanoma and breast cancer, chemoimmunotherapy with BCG to prolong remission in acute myelogenous leukemia, and possibly the use of BCG as an adjuvant to control minimal residual disease. Aside from these situations, it is advisable to treat patients only on clearly defined experimental protocols.     

Monoclonal antibodies in cancer immunotherapy.

The preceding article focused on some novel approaches for the adjuvant treatment of human melanoma and neuroblastoma with mAbs against antigens preferentially expressed on these tumors. It should be emphasized that the major goal of the immunotherapy modalities described here is to apply them in an adjuvant setting for the treatment of micrometastases. The major aim is to decrease the rate of development of metastases in a setting of very low tumor burden and ultimately achieve a prolongation in life span. The combination of powerful modern technologies achieving genetic engineering of mAbs, resulting in more human-like molecules, will lead to a reevaluation of these reagents alone or in combination with molecularly defined cytokines and growth factors for the immunotherapy of cancer. The initial, albeit anectodal, findings, of phase I clinical trials mentioned in this article lead to cautious optimism that immunotherapy may find a place and will eventually contribute to the adjuvant treatment of cancer.     

Thirty years of BCG immunotherapy for non-muscle invasive bladder cancer: a success story with room for improvement.

Over the last three decades, intravesical immunotherapy with the biological response modifier Mycobacterium bovis bacillus Calmette-Guérin (BCG) has been established as the most effective adjuvant treatment for preventing local recurrences and tumor progression following transurethral resection of non-muscle invasive bladder cancer. A large number of clinical trials have established a major role for BCG immunotherapy in urological oncology. In parallel, the major principles of the immunological mechanism have been revealed. In spite of this success, questions still remain regarding its clinical use, mechanism of action and potential improvement. This review provides a comprehensive insight into the historical era of BCG immunotherapy, the current indications for clinical application, the complex mechanism of action and possible future developments.     

Recent developments in renal cell cancer immunotherapy

Various immunotherapeutic approaches for the treatment of renal cell carcinoma (RCC) have been developed for > 90 years. Existing immunotherapeutic strategies against RCC include: systemic administration of cytokines; therapeutic vaccines based on tumor cells or dendritic cells; monoclonal antibodies; and adoptive immunotherapy (T cell transfer or allogeneic hematopoietic cell transplantation). However, the overall efficacy of immunotherapy for advanced RCC remains moderate. With the advent of molecularly targeted biological therapies that turned out to be significantly effective in the treatment of metastatic RCC, to many oncologists immunotherapy may seem to be moving into the periphery of RCC treatment strategies. However, for the last 2 years there has been significant progress made in immunotherapeutic approaches for the treatment of RCC. Immunotherapy still remains the only systemic therapeutic strategy that is believed to potentially cure RCC patients. The development of active and passive specific immunotherapeutic approaches, along with the possibility to 'switch off' particular immunosuppressive mechanisms (e.g., elimination of regulatory T cells, blockage of cytotoxic T lymphocyte antigen-4 signaling), have paved the way for future trials of new immunotherapies of RCC. However, the new studies will have to enroll optimally selected patients (nephrectomized, with non-massive metastases and good performance status) and will use tumor response criteria that are specifically optimized for clinical trials of immunotherapy.     

Recent developments in renal cell cancer immunotherapy

Various immunotherapeutic approaches for the treatment of renal cell carcinoma (RCC) have been developed for > 90 years. Existing immunotherapeutic strategies against RCC include: systemic administration of cytokines; therapeutic vaccines based on tumor cells or dendritic cells; monoclonal antibodies; and adoptive immunotherapy (T cell transfer or allogeneic hematopoietic cell transplantation). However, the overall efficacy of immunotherapy for advanced RCC remains moderate. With the advent of molecularly targeted biological therapies that turned out to be significantly effective in the treatment of metastatic RCC, to many oncologists immunotherapy may seem to be moving into the periphery of RCC treatment strategies. However, for the last 2 years there has been significant progress made in immunotherapeutic approaches for the treatment of RCC. Immunotherapy still remains the only systemic therapeutic strategy that is believed to potentially cure RCC patients. The development of active and passive specific immunotherapeutic approaches, along with the possibility to ‘switch off’ particular immunosuppressive mechanisms (e.g., elimination of regulatory T cells, blockage of cytotoxic T lymphocyte antigen-4 signaling), have paved the way for future trials of new immunotherapies of RCC. However, the new studies will have to enroll optimally selected patients (nephrectomized, with non-massive metastases and good performance status) and will use tumor response criteria that are specifically optimized for clinical trials of immunotherapy.     

M-Vax: an autologous, hapten-modified vaccine for human cancer

A novel approach to active immunotherapy has been devised based on modification of autologous cancer cells with the hapten, dinitrophenyl (DNP). This technology is being developed by AVAX Technologies as a treatment for melanoma under the brand name, M-Vax(TM). The treatment program consists of multiple intradermal injections of DNP-modified autologous tumour cells mixed with Bacille Calmette-Guérin (BCG). DNP-vaccine administration to patients with metastatic melanoma induces a unique reaction - the development of inflammation in metastatic masses. The inflammation is mediated by IFN-gamma-producing T-lymphocytes, some of which represent expansion of novel clones. Following DNP-vaccine treatment, almost all patients develop delayed-type hypersensitivity (DTH) to autologous, DNP-modified melanoma cells; approximately half also exhibit DTH to autologous, unmodified tumour cells. The toxicity of the vaccine is mild, consisting mainly of papules or pustules at the injection sites. Clinical trials have been conducted in two populations of melanoma patients: stage IV with measurable metastases and clinical stage III patients, rendered tumour-free by lymphadenectomy. In 83 patients with measurable metastases, there were 11 antitumour responses: two complete responses (CRs), four partial responses (PRs) and five mixed. Both CRs and two of four PRs occurred in patients with lung metastases. In 214 stage III patients the 5-year overall survival rate was 46% (one nodal site = 48%, in-transit metastases = 50%, two nodal sites = 36%). In both populations, the induction of DTH to unmodified autologous tumour cells was associated with significantly longer survival. This technology is applicable to other human cancers and clinical trials have been initiated with ovarian adenocarcinoma. There appear to be no insurmountable impediments to applying this approach to much larger numbers of patients or to developing it as a standard cancer treatment.     

M-Vax: an autologous,hapten-modified vaccine for human cancer

A novel approach to active immunotherapy has been devised based on modification of autologous cancer cells with the hapten, dinitrophenyl (DNP). This technology is being developed by AVAX Technologies as a treatment for melanoma under the brand name, M-Vax^TM. The treatment program consists of multiple intradermal injections of DNP-modified autologous tumour cells mixed with Bacille Calmette-Guérin (BCG). DNP-vaccine administration to patients with metastatic melanoma induces a unique reaction – the development of inflammation in metastatic masses. The inflammation is mediated by IFN-γ-producing T-lymphocytes, some of which represent expansion of novel clones. Following DNP-vaccine treatment, almost all patients develop delayed-type hypersensitivity (DTH) to autologous, DNP-modified melanoma cells; approximately half also exhibit DTH to autologous, unmodified tumour cells. The toxicity of the vaccine is mild, consisting mainly of papules or pustules at the injection sites. Clinical trials have been conducted in two populations of melanoma patients: stage IV with measurable metastases and clinical stage III patients, rendered tumour-free by lymphadenectomy. In 83 patients with measurable metastases, there were 11 antitumour responses: two complete responses (CRs), four partial responses (PRs) and five mixed. Both CRs and two of four PRs occurred in patients with lung metastases. In 214 stage III patients the 5-year overall survival rate was 46% (one nodal site = 48%, in-transit metastases = 50%, two nodal sites = 36%). In both populations, the induction of DTH to unmodified autologous tumour cells was associated with significantly longer survival. This technology is applicable to other human cancers and clinical trials have been initiated with ovarian adenocarcinoma. There appear to be no insurmountable impediments to applying this approach to much larger numbers of patients or to developing it as a standard cancer treatment.     

Immunocytokines: A Promising Approach to Cancer Immunotherapy

Recombinant antibody-cytokine fusion proteins are immunocytokines that achieve high cytokine concentrations in the tumor microenvironment and thereby effectively stimulate cellular immune responses against malignancies. The activation and expansion of immune effector cells, such as CD8⁺ T lymphocytes, by interleukin-2 immunocytokines resulted in the eradication of established pulmonary and hepatic metastases of murine melanoma and colorectal carcinoma in syngeneic mouse models. These immunocytokines were equally effective in eliminating established bone marrow and liver metastases of murine neuroblastoma by activating natural killer cells. The effective eradication of metastases by immunocytokines resulted in significant prolongation in life span of mice over that of controls receiving equivalent mixtures of antibody and interleukin-2, which failed to reduce the growth of disseminated metastases. Proof of concept was established, indicating that immunocytokine-induced activation and expansion of immune effector cells in the tumor microenvironment can effectively eradicate established tumor metastases. This promising new approach to cancer immunotherapy may lead to clinical applications that improve treatment of cancer patients with minimal residual disease in an adjuvant setting.     

Biological therapy: chronicling 15 years of progress

ABSTRACT

Introduction: Intralesional immunotherapy supplements systemic treatments and often achieves higher remission rates as compared to systemic therapy. Its indication is metastatic melanoma with limited tumor burden, particularly in loco-regional metastasis and distant soft tissue metastasis.

Areas covered: This review describes intralesional immunotherapy with talimogene laherparepvec (T-VEC), with velimogene aliplasmid (Allovectin-7) and with intralesional interleukin-2. These therapies function exclusively by activating the immune system. Furthermore, Rose Bengal and electrochemotherapy have been included, as bystander effects have been observed with these treatments.

Expert opinion: Objective remissions are achieved in a higher percentage with intralesional immunotherapies, such as intralesional interleukin-2 with up to 69% of complete remissions, as compared to systemic treatment. Therefore, intralesional immunotherapy may act as supplement in the armament against metastatic melanoma. In particular, for patients with multiple cutaneous and subcutaneous metastases (20—≥ 100) and in patients with subcutaneous bulky disease intralesional immunotherapy can improve the disease outcome. The exact role of intralesional immunotherapy in the age of immune checkpoint blockade has still to be determined. A number of clinical trials are on the way in order to better understand synergistic actions of intralesional and systemic immunotherapy.     

Allovectin-7 therapy in metastatic melanoma

Background: Patients with metastatic melanoma are immunosuppressed by the growing tumor. Allovectin-7 therapy is a form of active immunotherapy that aims at immunization of the host with substances designed to elicit an immune reaction that will eliminate or slow down the growth and spread of the cancer. Objective: to describe the rationale for immunotherapy with Allovectin-7 and assess its safety profile and efficacy based on the results of completed melanoma clinical trials. Methods: we reviewed both the published medical literature and the results of trials pending publication. Results/conclusion: Allovectin-7 is a safe and active immunotherapeutic agent. It induces local and systemic durable responses in patients with metastatic melanoma.     

Adjuvant immunotherapy with tumor infiltrating lymphocytes and interleukin-2 in patients with resected stage III and IV melanoma

Adoptive immunotherapy with tumor infiltrating lymphocytes (TIL) and interleukin (IL)-2 is reasonably effective in the treatment of patients with advanced melanoma. However, theoretically it should be of greater benefit as adjuvant therapy, especially in high-risk stages (resected stages III and IV). In a preliminary study, 25 patients (aged 23-72 years) with stage III-IV melanoma who underwent resection of metachronous metastases were reinfused with TIL cultivated and expanded in vitro with IL-2 from surgically removed metastases. IL-2 (starting dose 12 x 10 IU/m ) was co-administered as a continuous infusion according to West's scheme. A total of 8/22 (36.3%) evaluable patients were disease-free (DF) at a median follow-up of 5 years. DF survival (DFS) and overall survival (OS) rates were 44% and 37%, respectively, at 2 years, and 52% and 45% at 3 years. The CNS was the only site of disease recurrence in 57% of patients who relapsed. DF patients received a higher median dose of IL-2 than those who progressed (total dose 110 x 10 versus 86 x 10 IU/m, respectively). The progressive reduction in IL-2 dosage allowed all patients to complete treatment without permanent grade 4 toxicity. Analysis of tumor immunosuppression factors in lymphocytes inside the tumor (TCR zeta and epsilon chains, p56, FAS, and FAS-ligand) confirmed that the immunologic potential of TIL, depressed at the time of metastasectomy, was significantly restored after in vitro culture with IL-2. Adoptive immunotherapy with TIL and IL-2 could improve DFS and OS, although further work is required to determine its role in the treatment of patients with high-risk melanoma.     

The immunotherapy of patients with ovarian cancer

Ovarian cancer is a leading cause of cancer mortality. Chemotherapy is effective in reducing tumor burden in a majority of patients, however, only approximately 20% of advanced disease patients will ultimately survive tumor free, and further treatment options are needed. Continuing advances in immunology make immunotherapy a promising area for future research. The design of immunotherapy strategies for ovarian cancer requires an understanding of the immune microenvironment of the peritoneal cavity, which is frequently involved with ovarian cancer metastases and is the site of its most devastating effects. Immunotherapy approaches for ovarian cancer include locoregional and systemic cytokine therapies, prophylactic and therapeutic vaccines, and adoptive immunotherapy strategies. This review will summarize previous clinical trials as well as future directions for research. Further progress in T-cell specific immune responses will require the identification of specific ovarian cancer antigens that are processed and presented on the surface of tumor cells in the context of specific HLA molecules. In addition, a more detailed understanding of functional relations between the peritoneal microenvironment and the metastatic process is required.     

Recombinant human granulocyte macrophage-colony stimulating factor (rhGM-CSF) and autologous melanoma vaccine mediate tumor regression in patients with metastatic melanoma

In mice, significant immunoprotection was achieved using B16 melanoma cells transfected with granulocyte-macrophage colony-stimulating factor (GM-CSF) as vaccines (Dranoff G, Jaffee E, Lazenby A, et al. Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity. Proc Natl Acad Sci USA 1993;90:3539-43). The aim of this study is to test the hypothesis that recombinant human GM-CSF (rhGM-CSF) injected with autologous melanoma vaccine may result in tumor rejection in melanoma patients. Twenty stage IV melanoma patients were treated as outpatients with multiple cycles of autologous melanoma vaccine and bacillus Calmette-Guérin (BCG) plus rhGM-CSF injection in the vaccine sites. Two patients (10%) showed a complete response, with one patient showing resolution of subcutaneous, hepatic, and splenic metastases. In the second patient, buccal, subcutaneous, pulmonary, paraaortic, hepatic, splenic, and retroperitoneal metastases regressed completely. Two patients (10%) showed partial response, with regression of a paraaortic metastasis in one patient. In the second patient, there was shrinkage (> 75%) of a large hepatic lesion. One patient has been rendered free of disease after resection of a single pulmonary metastatic nodule. Three patients (15%) had stable disease during treatment but subsequently developed progression of disease. In 12 patients (60%), the disease progressed. Side effects were minimal. In a separate pilot study, 15 stage IV melanoma patients were also treated with autologous melanoma vaccine with BCG but not with rhGM-CSF; none responded. The fact that four patients showed objective responses to active specific immunotherapy with rhGM-CSF demonstrates that melanoma patients bearing a significant tumor burden may respond specifically to their autologous melanoma.     

Urinary markers of malignancy

Transitional cell carcinoma (TCC) is the second most common malignancy in the genitourinary tract. The majority of urothelial tumors are superficial when the patient first presents, but despite adequate resection of the primary lesion the recurrence rate is particularly high. In a small but significant group of patients the tumor is primary invasive or subsequently can progress and leads to death. Voided urine can be easily obtained and therefore diagnostic urine tests would be ideal for screening or follow up of TCC. Although many urinary markers have been described, none of them is used routinely in clinical practice. Promising tumor markers still need to be evaluated in multi-center clinical studies. Larger prospective trials are necessary in order to identify prognostic indicators that would help to predict disease progression or response to different treatment modalities (BCG, chemo-, radiotherapy, etc.). Hopefully, new diagnostic urine tests will allow to identify patients who will most benefit from early cystectomy with or without adjuvant treatment, bladder sparing protocols or systemic treatment. In this paper we have reviewed the literature and discuss, from the clinician's point of view, the current status of various diagnostic tests for urinary markers. [Lee SJ, Lee WE, Chang SG, Lee CH, Kim JI. A comparative study of telomerase, Lewis X, BTA, NMP22 and urinary cytology in bladder tumor. J Urol 1999;161(suppl):152.]     

Adjuvant intravesical therapy for superficial bladder cancer.

OBJECTIVE: To review the results of clinical trials and adverse drug effects of thiotepa, BCG vaccine, mitomycin, and doxorubicin, which are used as adjuvant intravesical therapy for superficial bladder cancer. DATA SOURCE: Information was retrieved from a MEDLINE search, of the English-language literature. Indexing terms included adjuvant pharmaceutics, bladder neoplasms, thiotepa, mitomycin, BCG vaccine, and doxorubicin. DATA EXTRACTION: Data from several human and in vitro studies were assessed and evaluated, according to the strength of comparative data and therapeutic response. STUDY SELECTION: Emphasis was placed on clinical trials that assessed and evaluated dosage, therapeutic regimens, and therapeutic response of adjuvant intravesical therapy for superficial bladder cancer. DATA SYNTHESIS: Adjuvant intravesical therapy and long-term prophylaxis are effective for superficial bladder cancer. Studies have shown that doxorubicin, thiotepa, BCG, and mitomycin, when used as adjuvant therapy, provide better protection than transurethral resection alone against tumor recurrence and prolong the time to when cystectomy is required. CONCLUSIONS: Several randomized clinical trials suggest that BCG is superior to thiotepa, doxorubicin, and mitomycin in preventing bladder tumor recurrence and tumor progression. Local cystitis is an adverse effect produced by all four agents; however, BCG vaccine has been reported to cause a higher incidence of adverse reactions (e.g., dysuria, hematuria). BCG may also cause an influenza-like syndrome, arthralgias, and fever, but most of these reactions have resulted in few severe adverse effects when the drug is given in the relatively modest recommended doses.     

Biomarkers in melanoma: staging,prognosis and detection of early metastases

Currently, melanoma remains a surgical disease since early detection and excision of thin melanomas offers the best chance of a cure. Despite intensive clinical investigation, no effective systemic therapies exist for metastatic melanoma. Sentinel lymph node biopsy has greatly aided the staging and prognostic evaluation of primary cutaneous melanoma, however, approximately a third of patients diagnosed with metastatic melanomas present without prior regional lymph node involvement. Additional prognostic biomarkers exist which help determine the risk of advanced melanoma but the accuracy for each current marker is less than 100%. A greater understanding of the biology of melanomas and the development of new methods to identify patients with early (subclinical) metastatic disease may allow for selective and more effective therapy for patients at-risk for advanced disease. In this paper, current and novel potentially more accurate biomarkers for the staging and prognostic evaluation of melanoma patients, and for the detection of subclinical metastases are reviewed.     

Intralesional immunotherapy of melanoma with BCG.

Treatment of recurrent cutaneous melanoma nodules with BCG is an effective and relatively nonmorbid method for eliminating these tumor nodules. Injected nodules can be made to disappear about 90 per cent of the time and in about 20 per cent of patients non-injected nodules in the same drainage area may also regress. Subcutaneous melanoma nodules are far more resistant to melanoma injection. Although cutaneous nodules can be made to regress there is no evidence that a systemic effect against disseminated melanoma exists and no responses of distant visceral disease have been seen following intralesional therapy of cutaneous nodules. The regression of cutaneous nodules following BCG injection appears to be an immunologic phenomenon and is related to the immunocompetence of the patient. The molecular mechanisms of this tumor regression are unknown and are the subject of intensive study. Several new approaches such as the use of BCG for the treatment of poor prognosis primary malignant melanomas, as well as the use of nonviable, nonbacteriologic agents for intralesional treatment are under investigation.     

肿瘤免疫治疗机制及乳腺癌免疫治疗进展

肿瘤的发生、发展与肿瘤及微环境之间所形成的肿瘤生态系统密不可分,基础研究成果的临床转化促使乳腺肿瘤医师能够更系统、更全面的去探索和制定有效的治疗方案。基于此,免疫治疗的日渐兴起正在改变乳腺癌系统治疗的格局,免疫治疗联合传统治疗方案,可进一步改善乳腺癌患者的预后。发现新的免疫治疗靶点、寻找更优的预测抗肿瘤免疫治疗效果的生物标志物和目标人群,是未来提升临床乳腺癌抗肿瘤免疫治疗效果的重要探索方向。     

Malignant melanoma

There have been many prospective randomized clinical trials of IFNalpha as post-surgical adjuvant therapy for high-risk melanoma patients. High dose IFNalpha therapy(HDI) has been reported to be effective in disease-free survival (DFS). However, the usefulness of HDI therapy is still controversial due to its grave toxicity. Low dose IFNalpha therapy (LDI) has no consistent effects on DFS. Most trials showed little activity in patients with metastatic melanoma. In Japan, IFNbeta, in combination with chemotherapy, has been used as post-surgical adjuvant therapy, and has been considered to improve the prognosis of stage III melanoma patients. In addition, we have recently performed a phase I/IIa trial of IFNbeta gene therapy for advanced melanoma patients.