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In less than 10 years, immunotherapy has revolutionized the fight against cancer. Among its various approaches, CAR-Ts, which combine gene therapy and cell therapy to provide patients with a personalized weapon against their cancer. It is a real therapeutic revolution. Already used in the treatment of leukemia in children and young adults and lymphoma in adults, it is intended to be developed for other forms of cancer. Although CAR-T cell therapy has shown significant clinical efficacy in blood cancers, it still faces major challenges in solid tumors. Recently, the company BioNTech – the company that developed the vaccine against COVID-19, with Pfizer – presented promising results on the addition of an mRNA vaccine to CAR-T cell therapy to treat this type of tumors.
CAR-T cell therapy consists of taking white blood cells specialized in the recognition and destruction of pathogenic cells (T lymphocytes) from the patient, then “improving” them by modifying their genetic heritage, making them multiply, and finally to reinject them into the patient, so that they destroy the tumor cells present in his body.
This genetic modification allows T cells to express a molecule that makes them particularly effective in identifying and eliminating cancer cells, called a “chimeric antigen receptor” or Chimeric antigen receptor (BECAUSE). CAR‑Ts are therefore T lymphocytes equipped with a CAR molecule adapted to the cancer to be treated.
Despite remarkable efficacy in certain hematological malignancies, in particular B acute lymphoblastic leukemia and other B lymphomas, the data in solid tumors remain rather disappointing, with at most some stabilization and rare positive responses observed. These solid tumors can develop in any tissue: skin, mucous membranes, bones, organs, etc. These are the most common since, alone, they represent 90% of human cancers. There are 2 types of tumours: carcinomas and sarcomas. The first come from epithelial cells (skin, mucous membranes, glands) — cancers of the breast, lungs, prostate, intestine, etc. The second, less frequent, come from connective tissue cells (known as “support” tissues) – cancers of bone, cartilage, etc.
Nevertheless, the ineffectiveness of CAR-T in solid tumors would be mainly due to the absence of specific membrane antigens on these tumors. Unlike haemopathies with restricted expression antigens such as CD19 or CD20, etc., membrane targets in solid tumors are often overexpressed by the tumor and are also found in various sometimes critical healthy tissues. CAR-Ts can therefore attack healthy tissues and jeopardize the patient’s prognosis.
In this context, after its success against COVID-19, the CEO of BioNTech, Dr. Ugur Sahin, says he wants to focus again on his first interest: cancer. Its research teams are trying the same mRNA technology that underpins the COVID-19 vaccine that BioNTech has brought to much of the world — with partner Pfizer — to try to improve cell therapies aimed at solid tumors, by associating an mRNA with CAR-Ts, and to stimulate a response by the patient’s immune system. The results of the phase 1/2 clinical trials were presented at the annual meeting of the American Association for Cancer Research (AACR), and the study on ClinicalTrials.gov.
Note that in 2021, the company initiated a Phase II cancer vaccine clinical trial by BioNTech, to evaluate the BNT111 mRNA-based therapy in combination with Libtayo (cemiplimab) in patients with melanoma. stage III or IV refractory to anti-PD1/unresectable relapse.
Two steps and one antigen
The experimental treatments used in the trial build on two previous works: BNT211 (BioNTech) — an autologous CAR-T cell therapy that targets the oncofetal antigen Claudin-6 (CLDN6) — and CARVac (BioNTech) — a vaccine based on mRNA encoding CLDN6 designed to enhance the activity of modified T cells.
As Haanen, an oncologist from the Netherlands Cancer Institute working on the new mRNA research, explained in a statement: One of the main limitations is that most of the proteins found on solid tumors that could be used as targets are also found at low levels on normal cells, making it difficult to specifically target CAR-T cells against cells. tumors and spare healthy cells. Other challenges include the limited persistence of CAR-T cells seen in solid tumors and their difficulty in reaching tumors and penetrating the center of mass. “.
For its part, CLDN6 is therefore an attractive target for CAR-T therapy, since it is absent from healthy adult tissues, but is strongly expressed in certain cancers, notably of the testes and ovaries, both of which have been shown to have an expression high antigen.
Concerning CARVac, Haanen specifies: “ It was developed to target antigen presenting cells in lymphoid tissue after systemic administration. It stimulates expansion and persistence of CAR-T cells while enhancing their antitumor activity “. The idea behind the mRNA vaccine is therefore to expand the initial population of CAR-T cells and to remain at a high level and in a state of increased activity. This should help the modified cells enter a tumor and persist there, killing the cancer cells.
BioNTech’s new treatment requires a two-step process. First, a patient receives an infusion of CAR-T cells that can recognize and attack cancer. A few days later, the patient receives the mRNA vaccine, which carries the genetic code for Claudin-6. The idea being that immune cells known as antigen-presenting cells take up the vaccine, produce Claudin-6, and then present this protein to CAR-T cells circulating in the body. This should trigger the proliferation of modified T cells and the production of cytotoxic compounds capable of killing cancer cells.
Positive preliminary data
This first human trial of the experimental treatment involved 16 patients, according to two dosages of injected CAR-T, associated or not with the mRNA vaccine. Most subjects had testicular or ovarian cancer. About 40% of people in the trial developed an unwanted inflammatory side effect known as cytokine release syndrome — soluble messengers that mediate communication between immune cells. This excessive immune response is a common side effect of CAR-T cell therapy, but in this small trial, researchers ensured that it was manageable and not serious in patients. Only 14 of the patients treated in the trial were assessed for efficacy, 6 months after CAR-T infusion by the data cutoff date of March 10, 2022. They had a significant decrease in tumor size.
Specifically, first, six of 14 evaluable patients achieved a partial response six weeks after treatment, a rate of 43%. Among them, four received treatment with CAR-T alone, and two were treated with mRNA injection in addition. Second, five other study subjects — also including patients with endometrial cancer, fallopian tube cancer, sarcoma, and gastric cancer — showed stabilization of their disease, or even a decrease in certain targeted cancerous lesions. Taken together, these results give an overall cancer control rate of 86%.
Haanen points out: Although the data is very early, it is remarkable that all testicular cancer patients showed clinical benefit at dose level 2, and the responses we observed can be profound, including complete remission in Classes. I look forward to further evaluation of this exciting new modality for patients with solid tumors. “.
Nevertheless, infusion of CLDN6 CAR-T, alone or in combination with CARVac, appears safe and promising for patients with CLDN6 positive cancers. Hanen adds: CLDN6 has never been targeted before with cell therapy, but in our study, this approach already shows efficacy that may be better than data from other CAR T trials in solid tumors. “.
However, Haanen cautioned that these data are very early, with few patients having been treated, so no major conclusions can be drawn at this time. Indeed, these differing mRNA dose strategies in a variety of dosing regimens, ranging from one injection of mRNA every two weeks for 100 days, to one injection every six weeks, require further testing. Moreover, additional data from the ongoing trial will be available later this year, BioNTech said.