Luciana Bento

Nova estratégia para vacina contra o câncer é testada com sucesso – Notícias

 

Ao combinar diferentes linhagens de células tumorais geneticamente modificadas, cientistas de Campinas (SP) conseguiram resultados promissores no tratamento de tumores em camundongos. O objetivo da pesquisa, apoiada pela FAPESP, é desenvolver uma vacina capaz de estimular o sistema imune a combater o câncer.

 

O trabalho vem sendo conduzido no LNBio (Laboratório Nacional de Biociências), do CNPEM (Centro Nacional de Pesquisa em Energia e Materiais), durante o doutorado de Andrea Johanna Manrique Rincón, sob a coordenação de Marcio Chaim Bajgelman.

 

“Testamos várias combinações de linhagens tumorais geneticamente modificadas e algumas foram capazes de impedir totalmente o tumor de crescer. Os resultados sugerem que a resposta antitumoral induzida pelo tratamento é duradoura, o que seria interessante na prevenção de recidivas”, disse Bajgelman à Agência FAPESP.

 

Como explicou o pesquisador, o desenvolvimento de uma vacina contra o câncer é um objetivo buscado por diversos grupos no mundo desde os experimentos do norte-americano William B. Coley (1862-1936), que usava vacinas antitumorais derivadas de microrganismos no início do século 20.

 

O modelo mais bem estabelecido é a GVAX, vacina composta de células tumorais autólogas (do próprio indivíduo a ser tratado) geneticamente modificadas para secretar a citocina GM-CSF (fator de estimulação de colônias de granulócitos e macrófagos, na sigla em inglês) e irradiadas para evitar que se proliferem descontroladamente no organismo.

 

“A GVAX foi testada em um modelo tumoral em camundongos, no qual as células de melanoma [sem modificação] são injetadas na veia da cauda. O tumor se instala no pulmão e causa a morte do animal em cerca de 28 dias. Com a GVAX [aplicada após a doença ter sido induzida], foi possível reverter o quadro e aumentar a expectativa de vida nos animais desafiados”, contou Bajgelman

 

Embora a GVAX tenha apresentado resultados animadores em roedores, não foi observado o mesmo desempenho nos ensaios com humanos.

 

A citocina GM-CSF usada na GVAX é considerada um imunomodulador, pois estimula a proliferação e a maturação de diferentes tipos de células de defesa. Em seu laboratório no LNBio, Bajgelman desenvolveu outras duas linhagens de melanoma capazes de secretar substâncias imunomoduladoras, como o ligante de 4-1BB e o ligante de OX40L.

 

As modificações genéticas foram feitas com auxílio de vírus recombinantes, que infectam as células tumorais e levam para seu interior o gene que codifica o imunomodulador. Depois de estabelecidas, as linhagens modificadas foram expostas à radiação.

 

“Quando irradiamos as células tumorais modificadas elas perdem a capacidade de gerar tumor, mas ainda servem para estimular o sistema imune”, explicou.

 

A ideia, com o tratamento, é fazer com que os linfócitos T — células de defesa que coordenam a resposta antitumoral — passem a enxergar as células cancerosas como inimigos a serem combatidos.

 

De acordo com Bajgelman, dados da literatura científica indicam que portadores de câncer costumam apresentar concentrações elevadas de um tipo de linfócito conhecido como célula T regulatória (Treg), cujo papel é inibir a proliferação de outros tipos de linfócitos que poderiam atacar as células tumorais.

 

Em uma situação fisiológica, as células Treg têm a importante missão de trazer equilíbrio ao sistema imune, para que tecidos do organismo não sejam atacados desnecessariamente. Mas, em portadores de câncer, disse Bajgelman, elas podem ajudar a proteger o tumor.

 

“Os ligantes 4-1BB e OX40L podem interagir com receptores existentes na superfície da célula T fazendo com que sua ativação seja potencializada. Nossa estratégia foi gerar vacinas que secretam esses ligantes e combinar com a GVAX, que secreta GM-CSF”, disse Bajgelman.

 

A combinação, explicou o pesquisador, permite estimular duas etapas do ciclo imunológico antitumoral: ativa a célula dendrítica, que é responsável por “apresentar” ao linfócito T os antígenos do tumor, e coestimula as células T, impedindo que assumam o fenótipo imunossupressor.

 

Primeiros testes

 

 

Diferentes combinações das três linhagens tumorais modificadas foram testadas no LNBio, em experimentos com camundongos. Tumores foram induzidos por meio de injeções subcutâneas de células de melanoma na lateral do corpo.

 

“Cerca de dois dias depois de induzir o tumor iniciamos o tratamento com as vacinas. Foram três doses, com intervalos de dois dias cada”, contou o pesquisador.

 

“Testamos as três linhagens de maneira isolada e todas elas conseguiram reduzir o crescimento do tumor em comparação ao controle [animais que receberam apenas as células tumorais não modificadas]. Em um segundo ensaio, testamos combinações de duas linhagens e o tumor cresceu bem menos do que com a monoterapia. Em alguns casos, o tumor foi totalmente suprimido”, contou Bajgelman.

 

Já a combinação das três linhagens modificadas combinadas em um único tratamento apresentou bom resultado em ensaios in vitro, mas não teve o desempenho esperado nos testes com animais.

 

“Já haviam sido descritos na literatura científica ensaios com esses imunomoduladores feitos de maneira isolada. Nós testamos, pela primeira vez, as diferentes combinações de linhagens imunomodulatórias”, disse o pesquisador.

 

Em outro experimento, os animais que já haviam sido tratados com as combinações vacinais que impediram o crescimento do tumor foram novamente “desafiados” – 30 dias depois – com uma nova injeção de células tumorais não modificadas, com potencial de formar tumores.

 

“Os animais que não desenvolveram tumor no primeiro protocolo também não desenvolveram nesse segundo desafio. Parece que o organismo criou uma memória imunológica e foi capaz de eliminar as células assim que foram injetadas. Os roedores foram acompanhados por mais de um ano e não manifestaram a doença”, disse Bajgelman.

 

Na avaliação do cientista, esse tipo de estratégia poderia ser usado em sinergia com outros tratamentos, como a remoção cirúrgica do tumor e a quimioterapia.

 

“Não é raro sobrarem algumas células tumorais no organismo após o tratamento convencional. A imunoterapia poderia proteger o paciente contra recidivas.”

 

Os resultados dos testes com camundongos foram divulgados em artigo publicado na revista Frontiers of Immunology.

 

O grupo do LNBio pretende agora criar linhagens tumorais modificadas a partir de células humanas e iniciar os primeiros ensaios in vitro.

 

“Para isso estamos gerando os vírus recombinantes com genes humanos. A ideia é usar os mesmos imunomoduladores testados em camundongos”, contou Bajgelman.

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