RESUMEN
PURPOSE: Two clinical trials were conducted to evaluate the clinical efficacy and immunologic impact of vaccination against the tyrosinase protein plus systemic interleukin 2 (IL-2) administration in patients with advanced metastatic melanoma. EXPERIMENTAL DESIGN: Full-length tyrosinase was employed as an immunogen to induce diverse immunologic responses against a commonly expressed melanoma antigen. Heterologous prime/boost vaccination with recombinant vaccinia and fowlpox vectors encoding tyrosinase was first explored in a randomized three-arm phase II trial, in which vaccines were administered alone or concurrently with low-dose or high-dose IL-2. In a subsequent single cohort phase II trial, all patients received the same vaccines and high-dose IL-2 sequentially rather than concurrently. RESULTS: Among a total of 64 patients treated on these trials, 8 objective partial responses (12.5%) were observed, all in patients receiving high-dose IL-2. Additional patients showed evidence of lesional regression (mixed tumor response) or overall regression that did not achieve partial response status (minor response). In vitro evidence of enhanced immunity against tyrosinase following protocol treatments was documented in 3 of 49 (6%) patients tested serologically, 3 of 23 (13%) patients tested for T-cell recognition of individual tyrosinase peptides, and 4 of 16 (25%) patients tested for T-cell recognition of full-length tyrosinase protein with real-time reverse transcription-PCR techniques. CONCLUSIONS: Whereas prime/boost immunization with recombinant vaccinia and fowlpox viruses enhanced antityrosinase immunity in some patients with metastatic melanoma, it was ineffective alone in mediating clinical benefit, and in combination with IL-2 did not mediate clinical benefit significantly different from that expected from treatment with IL-2 alone.
Asunto(s)
Vacunas contra el Cáncer/inmunología , ADN Recombinante/inmunología , Inmunización Secundaria/métodos , Interleucina-2/uso terapéutico , Melanoma/terapia , Vacunación/métodos , Terapia Combinada , ADN Recombinante/genética , Vectores Genéticos/genética , Humanos , Esquemas de Inmunización , Inmunoglobulina G/sangre , Interferón gamma/genética , Interferón gamma/metabolismo , Interleucina-2/administración & dosificación , Melanoma/inmunología , Melanoma/patología , Monofenol Monooxigenasa/genética , Monofenol Monooxigenasa/inmunología , Monofenol Monooxigenasa/metabolismo , Metástasis de la Neoplasia , Poxviridae/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/metabolismo , Resultado del TratamientoRESUMEN
BACKGROUND: Combination biologic therapy is an emerging area of clinical development and the physiological and analytical impact of one treatment on the other requires careful assessment. Significant analytical challenges are associated with developing the corresponding pharmacokinetic assays and further challenges arise in interpreting the subsequent in vivo data, which may be confounded by immunogenicity to one or both of the biologics. RESULTS: A case study of two monoclonal antibody therapeutics, given in combination, is presented where the immunogenicity rates differed significantly when the drug(s) were administered as monotherapy or in combination. CONCLUSION: The interpretation of the in vivo data is inextricably linked to an in-depth understanding of the formats and performance attributes of the associated pharmacokinetic and immunogenicity assays.
Asunto(s)
Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacocinética , Interpretación Estadística de Datos , Inmunidad/inmunología , Animales , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/sangre , Quimioterapia Combinada , Ensayo de Inmunoadsorción Enzimática , Humanos , Macaca fascicularisRESUMEN
Poxvirus vaccine vectors, although capable of eliciting potent immune responses, pose serious health risks in immunosuppressed individuals. We therefore constructed five novel recombinant vaccinia virus vectors which contained overlapping deletions of coding regions for the B5R, B8R, B12R, B13R, B14R, B16R, B18R, and B19R immunomodulatory gene products and assessed them for both immunogenicity and pathogenicity. All five of these novel vectors elicited both cellular and humoral immunity to the inserted HIV-BH10 env comparable to that induced by the parental Wyeth strain vaccinia virus. However, deletion of these immunomodulatory genes did not increase the immunogenicity of these vectors compared with the parental vaccinia virus. Furthermore, four of these vectors were slightly less virulent and one was slightly more virulent than the Wyeth strain virus in neonatal mice. Attenuated poxviruses have potential use as safer alternatives to current replication-competent vaccinia virus. Improved vaccinia virus vectors can be generated by deleting additional genes to achieve a more significant viral attenuation.