Cancer information Cancer treatment

Immunotherapy. Part2

Several centers have investigated the immunogenicity of lysates derived from tumor cells infected with Newcastle disease virus, vaccinia virus, and vesicular stomatitis virus. A multicenter randomized controlled prospective clinical trial that enrolled 250 patients with resected moderate- to high-risk melanoma was recently reported demonstrating the lack of any therapeutic benefit of immunization with the Newcastle disease virus viral oncolysate approach. This is the only randomized controlled multicenter trial of a melanoma tumor cell vaccine reported in the literature. Our understanding of molecular biology of immune response to melanoma has increased greatly since the design of this trial. We know the importance of tumor cell expression of histocompatibility antigens (e.g., HLA-A2) that were lacking in this tumor vaccine, or costimulatory molecules (B7.1) that may have been suboptimal in the vaccine. Yet this trial demonstrates the approach that will be necessary to evaluate the most promising vaccine candidates in the adjuvant setting. As with the SWOG 9035 trial (see later), the eligibility criteria for this trial included T3 (AJCC IIA) lesions for which prognosis is more heterogeneous than for stage IIb or a stage III disease, and the sample size was insufficient to detect small benefits.
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The allogeneic tumor cell vaccine reported first by Mitchell and colleagues, admixed with the immunologic adjuvant Detox (Ribi Immunochem Res, Hamilton, MT) has been studied in a second large multicenter randomized trial that is enrolling moderate-risk T3 N0 patients, and will be completed in 2006. This study has been enlarged from its original goal to 600 patients to increase the power of the trial, and its ability to detect more subtle movements in relapse-free survival. In addition, the understanding of the nature of melanoma antigens recognized has moved forward rapidly, including the discovery of a number of peptide antigens whose recognition is restricted by the HLA-A2 allele, which was absent in the tumor cell lines employed in this vaccine trial.
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Another approach to increasing immune response has been to alter tumor cells by binding haptens to autologous tumor cells. Pilot single-institution data with haptenated autologous tumor cells have been intriguing but, to date, this type of vaccine has not been evaluated in a randomized controlled or multicenter trial, owing in part to the difficulty of manipulating autologous tumor cells for the vaccine.
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A variety of efforts are also underway to immunize melanoma patients with purified or partially purified preparations of potentially immunogenic molecules from melanoma cells. The rationale for this approach comes from the identification of antigens on melanoma cells that can be recognized by antibodies in sera or lymphocytes from patients with melanoma. A large experience using partially purified cultured allogeneic tumor cell antigens has been the stimulus for the initiation of controlled trials of one vaccine preparation derived from shed antigens of cultured melanoma cell lines. Gangliosides have been shown to induce antibody responses after immunization. Of particular interest is that the ganglioside GM2 induces IgM antibody responses in more than 80% of patients immunized with GM2 and BCG following cyclophosphamide treatment at low dose as an immunomodulator. A prospective randomized study evaluated the role of vaccination for 6 months against GM2 with BCG, in comparison to BCG alone, using low-dose cyclophosphamide pretreatment in both groups.
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Serologic studies have shown a favorable prognostic significance for the presence of anti-GM2 ganglioside antibodies, suggesting that the induction of antibodies against gangliosides may confer protection from relapse and mortality due to melanoma. However, native autologous antibody reactivity against GM2 is infrequently detected in patients with melanoma. A variety of vaccination programs utilizing intact autologous and allogeneic cells, and cell fractions derived from allogeneic melanoma cell lines, have been employed to increase immune responses to autologous melanoma cells. The most promising results from randomized controlled trials of vaccination have emerged from studies of purified ganglioside GM2. Livingston and colleagues have performed a series of trials employing autologous tumor cells, and more recently purified ganglioside preparations, with various immunologic adjuvants. The combination of BCG given together with ganglioside GM2 has been shown to induce the formation of increased titers of IgM antibodies in the majority of patients immunized (33 of 44).

Immunotherapy

Tumor vaccines have a long history, but the search for effective methods to induce active immunity against tumors has been difficult. Repeated attempts have been made to inhibit the outgrowth of tumors and influence the natural history of melanoma by immunization against tumor cells or extracts of tumor cells. More recently, purified antigens recognized by the host antibody response, as well as the epitopes defined by T-cell responses, have been identified and prepared for use as vaccines. In addition, genetically modified melanoma cells, recombinant vaccines, and antiidiotype antibodies that represent the antibody-recognized antigens of melanoma have entered into clinical trials. Evidence is mounting that vaccination can induce immune responses to melanoma. Efforts to vaccinate patients against the antigens of melanoma can be classified categorically into trials of allogeneic tumor cell immunization, autologous tumor cell immunization, and immunization against synthetic chemically defined antigens.
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The last category can be subclassified into approaches directed at the induction of antibody responses, such as the gangliosides noted below, and approaches directed at the induction of a T-cell response to antigens that may include either proteins or peptides. Formal phase III trials have been initiated to evaluate the potential efficacy of relatively few tumor vaccines as adjuvant therapy in high-risk patients.
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At this point, it remains unclear which approaches will be most effective. The multitude of different ongoing trials listed indicate that there is no consensus on vaccine strategies. Early clinical trials of each of the categories of vaccines have been conducted in patients with metastatic disease, for reasons of safety evaluation. Despite early concerns, no reports of tumor enhancement have been documented with the whole-cell vaccination trials conducted to date. Antitumor responses have been recorded in a small fraction of subjects with metastatic disease, receiving varied programs of tumor cell immunization against allogeneic tumor cells incorporating two of three cell lines of hapten-coupled autologous [autochthonous] tumor cells. Most subsequent clinical studies have been performed in patients after resection of regional lymph node metastases or high-risk primary lesions. A more interesting observation is that patients who develop evidence of immune responses have improved disease-free survival or overall survival. This intriguing correlation does not directly imply that vaccines improve the clinical course (for instance, patients who a priori have a better prognosis may be more likely to develop an immune response to vaccination), but is consistent with the hypothesis that an immune response induced by vaccination may have antitumor benefit. A number of problems exist in the construction of tumor vaccines, including the weak immunogenicity of tumor antigens, heterogeneity of tumor-restricted antigen expression in tumors, and the ability of tumors to escape any immune responses that may be induced naturally, or therapeutically. Most melanoma antigens on tumor cells are not tumor-restricted or specific (i.e., present only on cancer cells) but are shared with certain normal cells.
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Active specific vaccination trials in melanoma (as opposed to nonspecific vaccination with BCG) have progressed from the use of unmodified, irradiated allogeneic or autologous melanoma cells for immunization, either alone or in combination with BCG and other nonspecific immunomodulators. It has been difficult to demonstrate any benefit or specific immune responses in the course of these trials. One exception has been immune responses to gangliosides, the major acidic glycolipid of melanoma cells, in some patients immunized with selected allogeneic melanoma cells.
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Efforts have been made to improve immunogenicity of allogeneic tumor cells by treating with the enzyme neuraminidase to remove sialic acid residues from the cell surface. Strategies have been developed to augment the immune response to tumor antigens by infecting tumor cells with nonpathogenic viruses. Viral proteins presented on the cell membrane of tumors have been shown to augment the immunogenicity of tumor antigens.

Melanoma Program Trial

The WHO Melanoma Program Trial 16 has evaluated the efficacy of a lower, less-toxic dosage of IFN- alpha2a, given 3 MU/d subcutaneously three times weekly for 3 years versus observation. Of 444 patients who entered this trial, a majority exhibited extracapsular extranodal involvement, a pathologic variable that made patients ineligible for the trials of the US Cooperative groups previously noted. The analysis of WHO Trial 16 has been reported preliminarily at 22 months of follow-up, and in a subset analysis an interaction between age and gender and treatment was found. This interim analysis of subsets, defined by the presence or absence of extranodal extension, has suggested an influence of this therapy upon intranodal disease, and lack of any trend to benefit among patients with extracapsular extension. Subsequent reports of interim analyses of this trial at intervals up to 39 months median follow-up have suggested the absence of a significant impact upon either relapse-free or overall survival. Canadian cialis

In summary, the analyses of E1684, NCCTG 83-7052, and WHO 16, taken together, argue that IFN- alpha2b at higher dosages, delivered intravenously, may be necessary for the benefit observed in E1684. Equivalent dosages of IFN- alpha2a administered by the IM route for shorter periods have been less effective, and lower dosages of IFN- alpha2a administered by the subcutaneous route for longer periods have been ineffective to date. The approval of IFN- alpha2b for adjuvant therapy within 2 months of surgery of high-risk node-positive and deep primary melanoma is the first adjuvant therapy approved for melanoma, and the first new agent approved for therapy of this disease in any stage or setting, since dacarbazine.
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The evaluation of newer and potentially more effective biologic agents in the adjuvant setting has been pursued in multiple trials. SWOG 86-42 is a trial of IFN- alpha administered at dosages projected to be the optimal immunomodulatory dosages (0.2 mg/d sc qod for 1 year). IFN- alpha is among the most potent immunomodulators yet tested, and one for which initial hopes for adjuvant and metastatic disease applications were elevated even beyond IFN- alpha2. As previously noted, the therapeutic activity of IFN gamma in the advanced disease setting has been negligible. The recently published SWOG 86-42 trial demonstrates the lack of therapeutic benefit for this agent at the dosage tested, in either intermediate-risk stage II or stage III resected melanoma. Of concern is that the initial report of this trial suggested a potentially adverse impact of treatment that has not yet been confirmed. In any case, the unequivocal failure of IFN- gamma to improve relapse-free or overall survival in the adjuvant setting argues that the effects of the dose, route, and schedule of IFN- gamma and the monocyte activation and NK activation associated with IFN- alpha administered as in this trial are not sufficient to alter the outcome of this disease. The pleiotropic effects of IFN- alpha2b, which account for its therapeutic benefit in melanoma, have yet to be proven. In vivo activities that may be important range from a direct antiproliferative and cytotoxic action to immunopotentiation of T- or B-cell host responses, dendritic cell antigen presentation, anti-angiogenesis factor, and tumor-restricted antigen expression. These are being evaluated prospectively in the context of the recently completed intergroup trial (ECOG 1690/SWOG 91-11, CALGB 91-90).

In an accompanying editorial on the E1684 ECOG trial

In an accompanying editorial on the E1684 ECOG trial, Balch and Buzaid questioned the role of adjuvant IFN- alpha in a high risk for recurrence patient whose tumor is greater than 4.0 mm thick and lymph node examination is clinically negative. Although excluded from the ECOG eligibility criteria for the E1684 trial, these patients have a greater than 60% chance of harboring microscopic nodal metastases and therefore may benefit from adjuvant high-dose interferon therapy. Knowing the pathologic status of the regional nodes in patients with thick melanomas provides important prognostic information. Patients with thick melanomas who have negative nodes have a significantly better prognosis than those with positive nodes (58% to 71% versus 32% to 42%). The available data from the ECOG E1684 trial were derived from patients whose lymph node pathology was known. The benefit of this therapy was seen for patients who entered the trial with lymph node involvement by comparison with the small subgroup of patients with thick, lymph node negative tumors. These authors therefore recommended that patients with melanomas greater than 4.0 mm have a nodal staging procedure, preferably intraoperative lymphatic mapping and sentinel lymph node biopsy, since this is the least morbid approach. Extrapolation of the results of E1684 may be considered for patients with local recurrences, satellite lesions, or in-transit metastases. Important questions that remain to be answered are whether the high-dose intravenous induction is necessary (or may in fact be sufficient to obtain the benefit of the E1684 treatment) and whether more prolonged interferon administration would enhance the benefit. In addition, the question remains whether early IFN- alpha therapy (after microscopic nodal metastases are removed) is better than late adjuvant therapy (after grossly positive nodal disease is resected with a therapeutic node dissection).
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Only a small subset of patients who receive high-dose IFN- alpha2b therapy actually derived benefit from it. Serum markers of tumors may provide a key to the more selective application of adjuvant therapy. Tyrosinase (a key enzyme in melanin biosynthesis whose gene is actively expressed only in melanocytes, melanoma cells, and Schwann cells) may serve as a marker of early dissemination of disease to allow more selective use of adjuvant therapy in the future. Because melanocytes and melanoma cells do not usually circulate in the blood, the detection of tyrosinase mRNA by reverse transcriptase-polymerase chain reaction (RT-PCR) in blood is considered a potential indication of the presence of circulating melanoma cells. Patients who have a positive RT-PCR before starting therapy that subsequently becomes negative may be those who benefit from the therapy. Human Growth Hormone

The North Central Cancer Treatment Group (NCCTG 83-7052) evaluated the adjuvant role of IFN- alpha2a given at 20 MU/IM three times weekly for 3 months, versus observation in patients with 1.69-mm Breslow depth T3+ or T4, and N1 patients (subsets of AJCC stages IIA or IIB and III). An analysis of 260 evaluable patients who entered this trial demonstrates no significant prolongation of survival, or of relapse-free interval overall. Subset evaluation of patients in stage II as opposed to those in stage III participating in this trial reveals a potential impact in the latter, by Cox analysis.