University of São Paulo: In the future, cancer treatment should combine two types of immunotherapy, study suggests

Cancer immunotherapy is currently one of the most effective approaches to treating patients. In it, cancer cells are fought by the body’s own immune system. Despite clinical success, not all people respond satisfactorily to this type of intervention or, if they do, they only have short-term responses, in addition to many side effects.

But a systematic review of the literature, carried out by Rafaela Rossetti, a doctoral student at the Clinical Oncology, Stem Cells and Cell Therapy Program at the Faculty of Medicine of Ribeirão Preto (FMRP) at USP, observed that the combination of two treatments (known as immunological checkpoint and adoptive transfer of genetically modified T cells) may bring promising results.

The article Combination of genetically engineered T cells and immune checkpoint blockade for the treatment of cancer was published in January 2022 in the journal Immunotherapy Advances .

“These studies provide lessons on possible approaches to enhance the performance of immune system cells against cancer, making them more resistant to the immunosuppressive mechanisms [ which reduce the activity of this system ] imposed by the tumor microenvironment ”, explains Rafaela Rossetti to Jornal da USP .

T-CARs are T cells genetically modified in the laboratory to produce a type of protein known as CAR (which stands for Chimeric Antigen Receptor) before being cultured and “returned” to the sick person. There are six products approved by the Food and Drug Administration (FDA) – the American drug regulatory agency – for clinical use and available on the market.

“The use of these cells has provided impressive results for the treatment of blood cancer. On the other hand, there are still limitations in its effectiveness against solid tumors”, says Lucas Eduardo Botelho, coordinator of the Gene Transfer Laboratory at the Ribeirão Preto Blood Center and an associate researcher at the Cell Therapy Center (CTC), one of the Research, Innovation Centers and Diffusion (Cepids) funded by the São Paulo Research Foundation (Fapesp).

“The inefficiency is due, in part, to the immunosuppression mechanisms employed by tumors to escape the attack mediated by immune system cells”, says Botelho.

Blocking the immune checkpoint is based on a group of proteins present on the surface of T lymphocytes that need to be activated or inactivated to trigger an immune response. Previous studies, led by Americans and Japanese, have shown that cancer cells stimulate the expression of these proteins (called checkpoints ) and their ligands (triggers) in tumor tissue. As a result, tumors “turn off” the immune system, which favors cancer growth. The same scientists also demonstrated that the use of antibodies capable of inhibiting the interaction between checkpoints and their ligands restores the antitumor defense response, allowing the reactivation of T lymphocytes.

“This review aimed to assess whether blocking immunological checkpoints would be a promising way to increase the therapeutic efficacy of genetically modified T cells against solid neoplasms”, summarizes Botelho.

Preclinical and clinical trials
Systematic review is a research method that seeks to bring together similar studies by critically evaluating them in their methodology and bringing them together in a statistical analysis. By synthesizing similar and good quality studies, it is considered the best level of evidence for decision-making on treatments, according to Cochrane , a global network of researchers specializing in systematic review works.

To carry out this review, Rafaela and Botelho defined the main points to be addressed and each of them contributed to the bibliographic search, contextualization and writing on the chosen topics. “In this review, we sought to bring a compilation of studies that provided important insights, as well as pre-clinical and clinical studies published recently”, explains Rafaela Rossetti .

“The aim was to provide a more complete picture of the current scenario of using immune checkpoint inhibitors in combination with the infusion of genetically modified T cells for cancer treatment.” In the end, 112 articles were selected for the researcher’s work.

In her opinion, this work contributed to enriching the knowledge in the area and allowed to reflect on possible implementations in research that currently address mainly genetically modified T cells for the treatment of cancer, aiming at an improvement in the efficiency of these cells.

Butantan, USP and Hemocentro de Ribeirão develop innovative cancer therapy
The Cell Therapy Center was the pioneer in Brazil to establish an infrastructure for the study and clinical application of stem cells and, a few years ago, there was the incorporation of the use of genetically modified T cells to recognize and destroy tumor cells in the areas of research and development.

As a result, a platform was established for the production and clinical use of T cells expressing chimeric antigen receptors against the CD-19 protein (expressed in B-cell leukemias and lymphomas). “This study resulted in the first successful application of anti-CD-19 T-CAR cells for the compassionate treatment of lymphoma patients in Latin America,” says Botelho.

The Gene Transfer Laboratory of the Blood Center in Ribeirão Preto is making efforts to contribute to the expansion of the platform for the production and clinical use of CAR-T cells through the creation of molecular tools for quality control and pre-clinical tests, in addition to to develop new genetic constructs and strategies to improve the effectiveness and access of patients to this type of therapy.

Botelho says that, currently, there are projects underway to evaluate genetic constructs against three new targets expressed by tumor cells, including solid tumors. In addition, a gene editing platform for the generation of allogeneic T cells is under implementation.

This strategy can drastically reduce the costs of this technology, and allows cellular modifications capable of increasing its effectiveness through the deletion of genes that limit its antitumor activity, for example.

“The survey we carried out reinforces the idea that using gene editing tools to delete the molecular circuits involved in this interaction can result in a more effective product, as it no longer suffers the suppressive action of the tumor microenvironment”, emphasizes the last author of the study. “Certainly this information will be incorporated into our effort to develop the next generation of anticancer cellular immunotherapies”, he concludes.

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