RESUMO
PURPOSE: This three-arm randomized study compares response rates and overall survival of patients with metastatic renal cell cancer (RCC) receiving high-dose or one of two low-dose interleukin-2 (IL-2) regimens. PATIENTS AND METHODS: Patients with measurable metastatic RCC and a good performance status were randomized to receive either 720,000 U/kg (high-dose [HD]) or 72,000 U/kg (low-dose [LD]), both given by intravenous (IV) bolus every 8 hours. After randomly assigning 117 patients, a third arm of low-dose daily subcutaneous IL-2 was added, and an additional 283 patients were randomly assigned. RESULTS: A total of 156 patients were randomly assigned to HD IV IL-2, and 150 patients to LD IV IL-2. Toxicities were less frequent with LD IV IL-2 (especially hypotension), but there were no IL-2-related deaths in any arm. There was a higher response proportion with HD IV IL-2 (21%) versus LD IV IL-2 (13%; P =.048) but no overall survival difference. The response rate of subcutaneous IL-2 (10%, partial response and complete response) was similar to that of LD IV IL-2, differing from HD IV (P =.033). Response durability and survival in completely responding patients was superior with HD IV compared with LD IV therapy (P =.04). CONCLUSION: Major tumor regressions, as well as complete responses, were seen with all regimens tested. IL-2 was more clinically active at maximal doses, although this did not produce an overall survival benefit. The immunological factors which constrain the curative potential of IL-2 to only a small percentage of patients need to be further elucidated.
Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Interleucina-2/administração & dosagem , Neoplasias Renais/tratamento farmacológico , Feminino , Humanos , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Análise de SobrevidaRESUMO
PURPOSE: The purpose of this study was to evaluate the immunological responses and therapeutic effectiveness of immunization with fowlpox vaccines encoding the gp100 melanoma antigen in patients with metastatic melanoma. EXPERIMENTAL DESIGN: In three consecutive clinical trials, patients were immunized with recombinant fowlpox viruses encoding three different forms of the melanoma/melanocyte-associated antigen gp100: (a) the native, full-length gp100 molecule; (b) the gp100 molecule with two amino acids modified to increase binding to HLA-A*0201 molecules; and (c) a "minigene" construct encoding a single, modified epitope gp100:209-217(210M) targeted to the endoplasmic reticulum. The immunogenicity of these constructs was studied using peripheral blood mononuclear cells to measure epitope-specific release of IFN-gamma. RESULTS: Reactivity against gp100 was not seen in any patient before receiving fowlpox immunization. Whereas just one of seven patients developed reactivity after receiving fowlpox encoding native gp100, 10 of 14 patients who received fowlpox encoding the anchor modified full-length gp100 exhibited reactivity against the native gp100 molecule, and 12 of 16 patients were successfully immunized after inoculation with the modified minigene construct (p2 = 0.02). There was no difference in the latter group between those randomized to vaccination by i.v. or i.m. routes. There was one partial cancer regression in the group of 46 patients receiving virus in the absence of interleukin (IL)-2. Once patients showed evidence of progressive disease, they were eligible for "cross-over" treatment to IL-2 alone or with the fowlpox virus. None of the 13 patients receiving the full-length or modified full-length forms of gp100 responded when receiving IL-2, whereas 6 of 12 patients who received the fowlpox containing the minigene construct and then received IL-2 showed objective cancer regressions, including three patients with complete regression. CONCLUSIONS: These data underscore the importance of modifying anchor residues of nonmutated self-antigen peptides to generate cellular immune responses after immunization and support the further investigation of recombinant fowlpox viruses encoding modified epitopes administered in combination with IL-2.
Assuntos
Vírus da Varíola das Aves Domésticas/química , Melanoma/metabolismo , Glicoproteínas de Membrana/química , Proteínas de Neoplasias/química , Adulto , Idoso , Antígenos de Neoplasias/química , Linfócitos T CD8-Positivos/metabolismo , Vacinas Anticâncer , Linhagem Celular Tumoral , Epitopos/química , Feminino , Antígenos HLA-A/genética , Antígeno HLA-A2 , Humanos , Imunoglobulina G/química , Interferon gama/metabolismo , Interleucina-2/metabolismo , Masculino , Glicoproteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Proteínas de Neoplasias/metabolismo , Peptídeos/química , Vacinas/química , Vaccinia virus/metabolismo , Antígeno gp100 de MelanomaRESUMO
Cancer vaccines targeting CD8+ T cells have been successful in eliciting immunologic responses but disappointing in inducing clinical responses. Strong evidence supports the importance of CD4+ T cells in "helping" cytotoxic CD8+ cells in antitumor immunity. We report here on two consecutive clinical trials evaluating the impact of immunization with both human leukocyte antigen class I- and class II-restricted peptides from the gp100 melanoma antigen. In Protocol 1, 22 patients with metastatic melanoma were immunized with two modified class I A*0201-restricted peptides, gp100:209-217(210M) and MART-1:26-35(27L). In Protocol 2, 19 patients received the same class I-restricted peptides in combination with a class II DRB1*0401-restricted peptide, gp100:44-59. As assessed by in vitro sensitization assays using peripheral blood mononuclear cells (PBMC) against the native gp100:209-217 peptide, 95% of patients in Protocol 1 were successfully immunized after two vaccinations in contrast to 50% of patients in Protocol 2 (P(2) < 0.005). Furthermore, the degree of sensitization was significantly lower in patients in Protocol 2 (P = 0.01). Clinically, one patient in Protocol 2 had an objective response, and none did in Protocol 1. Thus, the addition of the class II-restricted peptide gp100:44-59 did not improve clinical response but might have diminished the immunologic response of circulating PBMC to the class I-restricted peptide gp100:209-217. The reasons for this decreased immune reactivity are unclear but may involve increased CD4+CD25+ regulatory T-cell activity, increased apoptosis of activated CD8+ T cells, or the trafficking of sensitized CD8+ reactive cells out of the peripheral blood. Moreover, the sequential, nonrandomized nature of patient enrollment for the two trials may account for the differences in immunologic response.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer , Genes MHC da Classe II , Genes MHC Classe I , Melanoma/química , Melanoma/terapia , Adulto , Idoso , Antígenos de Neoplasias , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Ensaios Clínicos como Assunto , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Interferon gama/metabolismo , Interleucina-2/uso terapêutico , Leucócitos Mononucleares/metabolismo , Antígeno MART-1 , Masculino , Glicoproteínas de Membrana/química , Pessoa de Meia-Idade , Proteínas de Neoplasias/química , Proteínas de Neoplasias/fisiologia , Peptídeos/química , Receptores de Interleucina-2/biossíntese , Resultado do Tratamento , Antígeno gp100 de MelanomaRESUMO
Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is a critical immunoregulatory molecule (expressed on activated T cells and a subset of regulatory T cells) capable of down-regulating T cell activation. Blockade of CTLA-4 has been shown in animal models to improve the effectiveness of cancer immunotherapy. We thus treated 14 patients with metastatic melanoma by using serial i.v. administration of a fully human anti-CTLA-4 antibody (MDX-010) in conjunction with s.c. vaccination with two modified HLA-A*0201-restricted peptides from the gp100 melanoma-associated antigen, gp100:209-217(210M) and gp100:280-288(288V). This blockade of CTLA-4 induced grade III/IV autoimmune manifestations in six patients (43%), including dermatitis, enterocolitis, hepatitis, and hypophysitis, and mediated objective cancer regression in three patients (21%; two complete and one partial responses). This study establishes CTLA-4 as an important molecule regulating tolerance to "self" antigens in humans and suggests a role for CTLA-4 blockade in breaking tolerance to human cancer antigens for cancer immunotherapy.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Anticorpos Antineoplásicos/uso terapêutico , Antígenos de Diferenciação/imunologia , Antígenos de Neoplasias/imunologia , Doenças Autoimunes/etiologia , Imunoterapia , Melanoma/terapia , Glicoproteínas de Membrana/imunologia , Proteínas de Neoplasias/imunologia , Fragmentos de Peptídeos/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Citotóxicos/imunologia , Vacinação , Adulto , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/imunologia , Anticorpos Antineoplásicos/efeitos adversos , Anticorpos Antineoplásicos/imunologia , Antígenos CD , Antígenos de Diferenciação/fisiologia , Antígenos de Neoplasias/administração & dosagem , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Antígeno CTLA-4 , Colite/etiologia , Colite/imunologia , Colite/patologia , Dermatite/etiologia , Dermatite/imunologia , Dermatite/patologia , Feminino , Antígeno HLA-A2/imunologia , Hepatite Autoimune/etiologia , Hepatite Autoimune/imunologia , Hepatite Autoimune/patologia , Humanos , Tolerância Imunológica/imunologia , Injeções Intravenosas , Injeções Subcutâneas , Ativação Linfocitária , Masculino , Melanoma/imunologia , Glicoproteínas de Membrana/química , Pessoa de Meia-Idade , Metástase Neoplásica , Proteínas de Neoplasias/química , Fragmentos de Peptídeos/administração & dosagem , Peptídeos , Terapia de Salvação , Vitiligo/etiologia , Vitiligo/imunologia , Vitiligo/patologia , Antígeno gp100 de MelanomaRESUMO
Immunization with plasmid DNA represents a theoretically attractive method for increasing T cell responses against cancer antigens. We administered plasmid DNA encoding the gp100 melanoma-melanocyte differentiation antigen to 22 patients with metastatic melanoma and evaluated immunologic and clinical responses. Patients were randomized to receive plasmid DNA either intradermally (n = 10) or intramuscularly (n = 12). One patient (4.5%) exhibited a partial response of several subcentimeter cutaneous nodules. All other patients had progressive disease. Of 13 patients with cells available before and after immunization, no patient exhibited evidence of the development of anti-gp100 cell responses using in vitro boost assays. The same assays were capable of demonstrating immunologic precursors after immunization with fowl poxvirus encoding gp100 or with gp100 peptides. We were thus unable to demonstrate significant clinical or immunologic responses to plasmid DNA encoding the "self" nonmutated gp100 tumor antigen.
Assuntos
Vacinas Anticâncer/imunologia , Vacinas Anticâncer/uso terapêutico , Melanoma/tratamento farmacológico , Glicoproteínas de Membrana/imunologia , Proteínas de Neoplasias/imunologia , Plasmídeos , Adulto , Idoso , Vacinas Anticâncer/administração & dosagem , Feminino , Humanos , Injeções Intradérmicas , Injeções Intramusculares , Injeções Subcutâneas , Leucócitos Mononucleares/imunologia , Masculino , Melanoma/imunologia , Melanoma/patologia , Glicoproteínas de Membrana/genética , Pessoa de Meia-Idade , Metástase Neoplásica , Proteínas de Neoplasias/genética , Plasmídeos/administração & dosagem , Falha de Tratamento , Vacinas de DNA/administração & dosagem , Vacinas de DNA/imunologia , Vacinas de DNA/uso terapêutico , Antígeno gp100 de MelanomaRESUMO
We report here the adoptive transfer, to patients with metastatic melanoma, of highly selected tumor-reactive T cells directed against overexpressed self-derived differentiation antigens after a nonmyeloablative conditioning regimen. This approach resulted in the persistent clonal repopulation of T cells in those cancer patients, with the transferred cells proliferating in vivo, displaying functional activity, and trafficking to tumor sites. This led to regression of the patients' metastatic melanoma as well as to the onset of autoimmune melanocyte destruction. This approach presents new possibilities for the treatment of patients with cancer as well as patients with human immunodeficiency virus-related acquired immunodeficiency syndrome and other infectious diseases.
Assuntos
Autoimunidade , Imunoterapia Adotiva , Linfócitos do Interstício Tumoral/imunologia , Melanoma/imunologia , Melanoma/terapia , Linfócitos T/imunologia , Adolescente , Adulto , Antígenos de Neoplasias , Linfócitos T CD8-Positivos/imunologia , Células Clonais , Citocinas/metabolismo , Feminino , Antígeno HLA-A2/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Humanos , Interleucina-2/uso terapêutico , Contagem de Linfócitos , Depleção Linfocítica , Antígeno MART-1 , Masculino , Melanócitos/imunologia , Melanoma/patologia , Melanoma/secundário , Pessoa de Meia-Idade , Proteínas de Neoplasias/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Resultado do TratamentoRESUMO
This report describes a phase I clinical trial using nonmyeloablative, lympho-depleting chemotherapy in combination with adoptive immunotherapy in patients with metastatic melanoma. The chemotherapy-conditioning schedule that induced transient lymphopenia consisted of cyclophosphamide (30 or 60 mg/kg per day for 2 days) followed by fludarabine (25 mg/m(2) per day for 5 days). Immunotherapy for all patients consisted of in vitro expanded, tumor-reactive, autologous T-cell clones selected for high avidity recognition of melanoma antigens. Cohorts of three to six patients each received either no interleukin (IL)-2, low-dose IL-2 (72,000 IU/kg intravenously three times a day to a maximum of 15 doses), or high-dose IL-2 (720,000 IU/kg intravenously three times a day for a maximum of 12 doses). The toxicities associated with this treatment were transient and included neutropenia and thrombocytopenia that resolved in all patients. High dose intravenous IL-2 was better tolerated by patients after chemotherapy than during previous immunotherapy cycles without chemotherapy. No patient exhibited an objective clinical response to treatment, although five patients demonstrated mixed responses or transient shrinkage of metastatic deposits. This study established a nonmyeloablative-conditioning regimen that could be safely administered in conjunction with adoptive T-cell transfer and IL-2 in patients with metastatic melanoma.