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Terça-feira, Maio 17, 2022

Imunoterapia personalizada pode ser usada para tratar câncer de mama metastático

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Câncer de mama antes e depois da imunoterapia

Mulher com câncer de mama apresentava lesões metastáticas na parede torácica (em cima, à esquerda) e no fígado (em baixo, à esquerda). Depois de receber a imunoterapia, os tumores encolheram completamente. Exames recentes (R) mostram que ela está livre do câncer mais de 5 anos depois. Crédito: Instituto Nacional do Câncer (NCI)

Uma forma experimental de imunoterapia que usa as próprias células imunes de combate ao tumor de um indivíduo poderia ser usada para tratar pessoas com câncer de mama metastático, de acordo com resultados de um ensaio clínico em andamento liderado por pesquisadores do Centro de Pesquisa do Câncer do Instituto Nacional do Câncer (NCI). , parte dos Institutos Nacionais de Saúde. Muitas pessoas com câncer de mama metastático podem desenvolver uma reação imune contra seus tumores, segundo o estudo, um pré-requisito para esse tipo de imunoterapia, que se baseia nos chamados linfócitos infiltrantes de tumor (TILs).

Em um ensaio clínico com 42 mulheres com câncer de mama metastático, 28 (ou 67%) geraram uma reação imune contra o câncer. A abordagem foi usada para tratar seis mulheres, metade das quais experimentou redução mensurável do tumor. Os resultados do julgamento apareceram em 1º de fevereiro de 2022, no Revista de Oncologia Clínica.

“É um dogma popular que os cânceres de mama positivos para receptores hormonais não são capazes de provocar uma resposta imune e não são suscetíveis à imunoterapia”, disse o líder do estudo Steven A. Rosenberg, MD, Ph.D., chefe do Ramo de Cirurgia no Centro do NCI para Pesquisa do Câncer. “As descobertas sugerem que esta forma de imunoterapia pode ser usada para tratar algumas pessoas com câncer de mama metastático que esgotaram todas as outras opções de tratamento”.

A imunoterapia é um tratamento que ajuda o próprio sistema imunológico de uma pessoa a combater o câncer. No entanto, a maioria das imunoterapias disponíveis, como os inibidores do checkpoint imunológico, mostraram eficácia limitada contra os cânceres de mama positivos para receptores hormonais, que são a maioria dos cânceres de mama.

A abordagem de imunoterapia usada no estudo foi iniciada no final da década de 1980 pelo Dr. Rosenberg e seus colegas do NCI. Baseia-se em TILs, células T que são encontradas dentro e ao redor do tumor.

Os TILs podem atingir células tumorais que possuem proteínas específicas em sua superfície, chamadas neoantígenos, que as células imunes reconhecem. Os neoantígenos são produzidos quando ocorrem mutações no tumor.[{” attribute=””>DNA. Other forms of immunotherapy have been found to be effective in treating cancers, such as melanoma, that have many mutations, and therefore many neoantigens. Its effectiveness in cancers that have fewer neoantigens, such as breast cancer, however, has been less clear. 

The results of the new study come from an ongoing phase 2 clinical trial being carried out by Dr. Rosenberg and his colleagues. This trial was designed to see if the immunotherapy approach could lead to tumor regressions in people with metastatic epithelial cancers, including breast cancer. In 2018, the researchers showed that one woman with metastatic breast cancer who was treated in this trial had complete tumor shrinkage, known as a complete response.

In the trial, the researchers used whole-genome sequencing to identify mutations in tumor samples from 42 women with metastatic breast cancer whose cancers had progressed despite all other treatments. The researchers then isolated TILs from the tumor samples and, in lab tests, tested their reactivity against neoantigens produced by the different mutations in the tumor.

Twenty-eight women had TILs that recognized at least one neoantigen. Nearly all the neoantigens identified were unique to each patient.

“It’s fascinating that the Achilles’ heel of these cancers can potentially be the very gene mutations that caused the cancer,” said Dr. Rosenberg. “Since that 2018 study, we now have information on 42 patients, showing that the majority give rise to immune reactions.”

For the six women treated, the researchers took the reactive TILs and grew them to large numbers in the lab. They then returned the immune cells to each patient via intravenous infusion. All the patients were also given four doses of the immune checkpoint inhibitor pembrolizumab (Keytruda) before the infusion to prevent the newly introduced T cells from becoming inactivated.

After the treatment, tumors shrank in three of the six women. One is the original woman reported in the 2018 study, who remains cancer free to this day. The other two women had tumor shrinkage of 52% and 69% after six months and 10 months, respectively. However, some disease returned and was surgically removed. Those women now have no evidence of cancer approximately five years and 3.5 years, respectively, after their TIL treatment.

The researchers acknowledged that the use of pembrolizumab, which has been approved for some early-stage breast cancers, may raise uncertainties about its influence on the outcome of TIL therapy. However, they said, treatment with such checkpoint inhibitors alone has not led to sustained tumor shrinkage in people with hormone receptor–positive metastatic breast cancer.

Dr. Rosenberg said that with the anticipated opening early this year of NCI’s new building devoted to cell-based therapies, he and his colleagues can begin treating more individuals with metastatic breast cancer as part of the ongoing clinical trial. He noted that this new immunotherapy approach could potentially be used for people with other types of cancer as well.

“We’re using a patient’s own lymphocytes as a drug to treat the cancer by targeting the unique mutations in that cancer,” he said. “This is a highly personalized treatment.”

Reference: “Breast Cancers are immunogenic: Immunologic analyses and a phase II pilot clinical trial using mutation-reactive lymphocytes” 1 February 2022, Journal of Clinical Oncology.





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