Systemic therapy for melanoma.

Advanced melanoma is a disease with a poor prognosis. Most of the currently available chemotherapy agents are ineffective. In contrast to other cancers, immune-based and novel, targeted therapies appear to have some effect in melanoma. Exciting research in the past few years holds hope for the future. We provide an overview of the current management principles of this condition with special emphasis on the emerging options in the systemic therapy of advanced disease.

Sheep erythrocyte demonstrated better effect than IL-2 and IFN-gamma as biological response modifier against glioma in experimental model.

The significant insights into the immunobiology of central nervous system (CNS) and brain tumor have opened up the feasibility of applying 'Immunotherapy' as an alternative to the poor prognosis of malignant brain tumor with conventional therapeutic approaches. Though cytokines like IL-2 and IFN-gamma used against glioma showed some favorable results by eliciting Th1 type immune response, a proper immunotherapeutic agent is still to be searched for. Sheep erythrocyte (SRBC), a corpuscular antigen showed a better therapeutic efficacy in terms of enhanced survival and augmentation of cell mediated immunity (CMI) in a glioma model developed by chemical carcinogen ethyl nitrosourea. Histological findings revealed most efficient glioma rejection in SRBC and combination biological response modifier (BRM) treated groups. Simultaneously E-rosetting, cytotoxicity of lymphocytes, phagocytosis and antigen presenting capacity of myeloid cells established the better therapeutic efficacy of SRBC alone than other BRMs viz. IL-2 and IFN-gamma. Even the effect of combination therapy of different BRMs showed marginal differences in facilitating glioma reduction than the single use of SRBC. These findings emphasized the application of SRBC as an exogenous BRM having the potential as a rational therapeutic adjunct against glioma.

No effect of interleukin-2 on IgE levels given in addition to antiretroviral therapy in HIV-infected adults with CD4 >300 cells/mm3.

HIV-infected patients may have frequent atopy caused by an imbalance of Th1 and Th2 cytokines. The objective of the present study was to investigate whether IL-2 given in addition to antiretrovirals (ARV) would result in lower IgE levels and less allergic symptoms. Patients naive to IL-2 (n=28) began IL-2 plus ARV and were followed for 12 months. IgE, eosinophil and CD4 counts, HIV RNA, symptom scoring, PFT and skin prick test (SPT) were performed. It was found that the baseline median CD4 and IgE were 386.5 cells/mm3 and 63.5 IU/ml, respectively. Four patients had allergic rhinitis (AR) and 61% had a positive SPT to at least 1 antigen. At month 12, patients had higher CD4 counts (p < 0.001) compared to the baseline; however, there were no differences in IgE levels, allergic symptom scores or HIV RNA. The eosinophil count was higher after IL-2 administration. It was concluded that IL-2 plus ARV resulted in higher CD4 counts but had no effect on atopy.

Retroviral-mediated IL-2 gene transfer into murine neuroblastoma

We used retroviral-mediated gene transfer of the human interleukin (IL)-2 gene into murine neuroblastoma cells to investigate whether locally-secreted IL-2 is able to influence the generation of anti-tumor immune responses. Supernatant obtained from cultures of approximately 1 x 10(6) IL-2 gene-transduced, G-418 selected neuro-2a cells was assayed for human IL-2 production by ELISA kit. First, to estimate whether the local secretion of IL-2 from the genetically-modified tumor cells would affect their tumorigenicity in vivo, IL-2-secreting neuro-2a cells were s.c. injected into A/J mice and tumor growth was measured weekly. And to estimate whether IL-2 transfected neuroblastoma cells protect mice from tumor development after wild-type tumor cell challenge, IL-2-secreting neuro-2a cells were s.c. injected into A/J mice. Seven days after IL-2 gene-transfected neuroblastoma cell injection, unmodified neuro-2a cells were s.c. injected into the contralateral site of A/J mice and tumor growth was measured weekly. Finally, to estimate IL-2 effect on pre-established large tumor burdens, IL-2-secreting neuro-2a cells were s.c. injected into A/J mice with established tumor and its growth was measured weekly. The IL-2 gene-transduced neuro-2a clones secreted 120.25-177.3 IU of IL-2 per ml per 10(6) cells during 24 hr. None of the mice injected with IL-2-secreting neuro-2a cells developed tumors within 6 weeks, while all of the mice injected with wild-type neuro-2a cells developed tumors. Immunization of mice with IL-2 gene-transfected, irradiated neuro-2a cells protected these animals against a subsequent challenge with wild-type tumor cells. Finally, the size of large neuroblastomas decreased after IL-2-secreting neuro-2a cell injection into mice. Local secretion of IL-2 gene-transduced tumor cells abrogates their tumorigenicity and induces protective immunity and may inhibit the growth of neuroblastoma.

Interleucina-2: una terapia alternativa en cáncer / Interleukin-2: an alternative therapy for cancer

Recientemente, se ha demostrado que la manifestación de inmunidad antitumoral resulta de las interacciones entre varias poblaciones celulares del sistema inmune. La inmunoterapia con interleucina-2 (IL-2) y células destructoras de linfocinas activadas generadas por linfocitos análogos ha producido regresiones significativas en tumore de pacientes con cáncer avanzado. El efecto mitogénico de la IL-2 en linfocitos T citolíticos de tumores-reactivos (CTL), destructores naturales y LAK puede incrementar el potencial de defensa en la expansión de tumores. A diferencia del tratamiento sistémico, la administración de IL-2 en la vecindad del tumor puede ofrecer ciertas ventajas, tales como: uso de dosis bajas y menos anticuerpos anti IL-2 y proveer un cambio de confrontación mucho mejor con inhibidores IL-2 y mecanismos de retroalimentación, los cuales podrán limitar sustancialmente los posibles efectos terapéuticos de la IL-2 en pacientes con tumores

Cutaneous hypersensitivity to co-trimoxazole after autologus bone marrow transplantation and immunotherapy with interferon alpha-2A and interleukin-2.

Typical cutaneous hypersensitivity reaction to co-trimoxazole was seen in a woman after autologous bone marrow transplantation and immunotherapy. She had developed no such reaction during chemotherapy prior to the transplant or immediately after the transplant. The immunoperturbed state that exists for a period of time after bone marrow transplantation, especially in the presence of immunomodulation caused by combined therapy with recombinant human interferon alpha and interleukin-2, with exposure to potentially reaginic agents may have contributed to the development of the hypersensitivity reaction in this patient.

Interleukin-2 in autologous bone marrow transplantation.

Interleukin-2 results in the generation of lymphokine activated killer cells which exhibit a potent effect against a wide variety of tumours. Consequently, interleukin-2 therapy has been used to induce a graft versus tumour effect following autologous bone marrow transplantation. Preclinical studies have shown that this results in successful engraftment, and an enhanced reconstitution of the immune system.

Characterization of the antitumor activity of a polyantigenic immunomodulator (PAI): I. Utilization of cimetidine and cyclosporine A

Hemos utilizado cimetidina (CMT), ciclosporina a (CsA) e interleuquina 2 (IL-2) para caracterizar el efecto anticanceroso de un inmunomodular poliantigéncio (polyantigenic immunomodulator, PAI). PAI consiste de una mezcla inactivada de bacterias y virus de influenza, emulsificada en una preparación de aceite de maní-arlacel A-monoesterato de alumini. La actividad antitumoral fue evaluada utilizando el tumor ascítico de Ehrlich implantado en ratones Swiss-Webster (alogenéicos) o C57BL/6J (singenéicos). La actividad antitumoral de PAI aumentó con la CMT actuando sinergisticamente al reducir sustancialmente el crecimiento tumoral e incrementar el porciento de sobrevivencia de los ratones, mientras que la CsA suprimió esta actividad. PAI o sus componentes individuales indujeron blastogénesis en linfocitos de bazo de ratón C57BL/6J e interleuquina 2 aumentó considerablemente esa respuesta. Los resultados sugieren que PAI actúa a nivel de la inmunidad celular

Structure-function relationships for the interleukin 2 receptor system

Receptors for interleukin 2 (IL-2) esit in at least three forms which differ in their subunit compositio, their affinity for ligand and their ability to mediate a cellular reponse. Type I receptors occur following cellular acitivation and consist of the 55,000 m. w. glycoprotein Tac. These receptors bind IL-2 with a low affinity, do not internalize ligand and have not been definitively associated with any response. Type II receptors, on the other hand, conssit of one or more glycoproteins of 70,000 m. w. which have been termed "beta ([beta]) chains." They bind IL-2 with an intermediate affinity and rapidly internalize the ligand. [Beta] proteins mediate many cellular IL-2-dependent reponses, including the short-term activation of natural killer cells and the induction of Tac protein expression. Type III receptors consist of a ternary complex of the Tac protein, the [beta] chain(s) and IL-2. They are characterized by a paricularly high affinity for ligand association. Type III receptors also internalize ligand and mediate IL-2-dependent responses at low factor concentrations. The identification of two independent IL-2-binding molecules, Tac and [beta], thus provides the elusive molecular explanation for the differences in IL-2 receptor affinity and suggests the potential for selective therapeutic manipulation of IL-2 reponses.

Imunoterapia ativa específica e imunoquimioterapia adotiva em tumores experimentais: açäo da interleukin - 2

Uma preparaçäo de proteínas de membrana plasmática de células tumorais obtidas por processo original de vesículaçäo de membrana celular é usada como antígeno específico do tumor. Em sistema singênico protegeu 80% dos camundongos contra inóculo tumoral. Inóculo tumoral jé estabelecido, em início de crescimento, é curado em 70 a 80% com inoculaçäo de antígeno de membrana com afjuvante, em tumores experimentais de camundongo. A imunoterapia adotiva específica, isto é, a transferência de linfócitos pré-sensibilizados, näo protegeu camundongos contra tumor já desenvolvido. A imunoquimioterapia adotiva, transferência de linfócitos de baço de animal imunizados pelo tumor + 1 dose de ciclofosfamida foi eficiente, curando 80% dos animais com tumor singênico já estabelecido, sendo que a ciclofosfamida apenas retarda temporariamente o crescimento tumoral. Este projeto näo tem aplicaçäo clínica, pois para o doente näo se dispöe de linfócitos isogênicos sensibilizados especialmente contra seu câncer. Está sendo tentada a substituiçäo de linfócitos T sensibilizados por "Interleukin-2" + ciclofosfamida. A "Interkeukin-2" é obtida in vitro por açäo de macrófago + linfócito T helper + concanavalina A. Experiência preliminares em tumores experimentais deram nítido retardamento do crecimento dos mesmos. Este produto está sendo purificado e concentrado e produzido especificamente com antígeno do próprio tumor