Predicting the Efficacy and Safety of TACTICs (Tumor Angiogenesis-Specific CAR-T Cells Impacting Cancers) Therapy for Soft Tissue Sarcoma Patients

Fujiwara, Kento; Sasawatari, Shigemi; Nakai, Sho; Imaeda, Keisuke; Nagai, Seina; Matsuno, Yoshihiro; Hatanaka, Kanako C.; Hatanaka, Yutaka; Takenaka, Satoshi; Okada, Naoki

doi:10.3390/cancers12102735

Cited by 7 publications

(3 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…CAR первого поколения характеризуются наличием только сигнального домена CD3, в то время как CAR второго и третьего поколений имеют костимуляторные домены, встроенные в цитоплазматическую область CAR, такие как 4-1BB (CD137), CD28, CD27, OX40 (CD134), ICOS (CD278), RIAD [1,66] [29,33,57,58] и VEGFR1 [104], интегрины, ассоциированные с нео-эндотелием [32], опухоль-специфичный сплайс-вариант фибронектина, содержащий экстра-домен B [102]. Данные антигенные молекулы, экспрессируемые эндотелиальными клетками аномальной сосудистой сети опухоли, представляют клинический интерес для терапии CAR-Т-клетками из-за геномной стабильности и относительной доступности для циркулирующих Т-клеток, а также их экспрессии в различных типах солидных опухолей [29,32,33,57,58,104]. Помимо прочего, использование подобных мишеней для CAR-Т-клеточной терапии позволяет направить миграцию адаптивно перенесенных эффекторов вглубь опухоли через неопластические кровеносные сосуды.…”

Section: т-клетки с генной модификацией рецептора для адаптивного пер...unclassified

Modern T cell technologies for immunotherapy of solid tumors

et al. 2023

View full text Add to dashboard Cite

According to the common concept of immune editing, the interaction of malignant tumor cells and immune system is a complex multifactorial process, which may result in both antitumor effector activity and development of suppressor mechanisms that promote tumor growth. Accumulation of scientific knowledge in the field of studying the antitumor immune response and tolerance has led to emergence of many research and therapeutic approaches that use different components of the immune system to combat neoplastic processes. Along with currently available approaches, there are strategies that use the potential of antigen-specific T lymphocytes, the main effectors of adaptive immunity, in order to fight malignant neoplasms which appeared more than a century ago and have built the scientific basis of cancer immunotherapy. One line of evidence of the significant antitumor potential of T cells in immunotherapeutic schemes for the cancer treatment was presented by successful therapy of hemato-oncological diseases, achieved at the end of the past decade. At the same time, however, the therapy of solid malignant neoplasms still faces significant difficulties that limit the efficiency of treatment. In this regard, the main objective of the review is to accumulate up-to-date information on the successes and limitations of T cell immunotherapy in the patients with solid tumors. To date, the phenotype and functionality of T cells is being investigated and modulated both towards enhancing antitumor cytotoxicity, increasing viability and proliferative activity of T cells, and in overcoming the immunosuppressive effect of the tumor and its tolerogenic microenvironment upon T cells, as well as ensuring targeted migration of the effector T cells to the malignant tissues. This review discusses immunotherapeutic approaches exploiting the potential of effector T lymphocytes, e.g., current clinical trials or applied therapeutic regimens for the treatment of solid malignant neoplasms. Antigen-independent approaches aimed at nonspecific enhancement of the T cell responses, i.e., therapy with recombinant cytokines and inhibition of immune checkpoint molecules. Antigendependent, or antigen-specific approaches such as adoptive T cell therapy with endogenous T lymphocytes are also discussed as well as trials on T cells with modified antigen-recognition receptor (CAR-Tcells, TCR-Tcells), like as usage of bispecific antibodies as T cell engagers. The review describes the benefits and disadvantages of these approaches in monotherapy, as well as current results and prospects for their mutual combinations.

show abstract

Section: т-клетки с генной модификацией рецептора для адаптивного пер...unclassified

Modern T cell technologies for immunotherapy of solid tumors

et al. 2023

View full text Add to dashboard Cite

show abstract

“…Focusing on the fact that the growth and survival of cancer cells depend on blood supply, we developed tumor angiogenesis-specific CAR-T cells impacting cancers (TACTICs) targeting vascular endothelial growth factor receptor-2 (VEGFR2), which is expressed at high levels in tumor vascular endothelial cells [ 8 ]. This therapy is efficacious in murine solid-tumor models, based on its ability to target tumor blood vessels and molecules associated with tumor blood-vessel injury.…”

Section: Introductionmentioning

confidence: 99%

“…During target selection, we found the sarcoma to be promising, since VEGFR2 is expressed at high levels not only in tumor neovascular tissues, but also in the tumor cells themselves. However, it has been suggested that anti-VEGFR2 CAR-T cells may also react strongly with some normal human tissues [ 8 ]; therefore, prior to TACTIC clinical trials, it is necessary to search for and create tumor vascular injury type CAR-T cells targeting safer molecules with very low expression in normal tissues. We therefore focused on roundabout homolog 4 (Robo4) [ 9 ], which is expressed in tumor vascular endothelial cells at high levels, as a novel target molecule [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Binding and Efficacy of Anti-Robo4 CAR-T Cells against Solid Tumors

et al. 2022

Self Cite

View full text Add to dashboard Cite

Chimeric antigen receptor expression T (CAR-T) cell therapy has been shown be efficacious against relapsed/refractory B-cell malignant lymphoma and has attracted attention as an innovative cancer treatment. However, cells of solid tumors are less accessible to CAR-T cells; moreover, CAR-T function is decreased in the immunosuppressive state of the tumor microenvironment. Since most tumors induce angiogenesis, we constructed CAR-T cells targeting roundabout homolog 4 (Robo4), which is expressed at high levels in tumor vascular endothelial cells, by incorporating three anti-Robo4 single-chain variable fragments (scFv) that were identified using phage display. We found that binding affinities of the three CARs to mouse and human Robo4 reflected their scFv affinities. More importantly, when each CAR-T cell was assayed in vitro, antigen-specific cytotoxicity, cytokine-producing ability, and proliferation were correlated with binding affinity for Robo4. In vivo, all three T-cells inhibited tumor growth in a B16BL6 murine model, which also correlated with Robo4 binding affinities. However, growth inhibition of mouse Robo4-expressing tumors was observed only in the model with CAR-T cells with the lowest Robo4 affinity. Therefore, at high Robo4 expression, CAR-T in vitro and in vivo were no longer correlated, suggesting that clinical tumors will require Robo4 expression assays.

show abstract