Overview of CD70-Targeted CAR Cell Therapies

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Backgrounds of CD70

CD70 is a single-chain membrane glycoprotein with a molecular weight of about 37 kDa. CD70 belongs to the tumor necrosis factor (TNF)/nerve growth factor (NGF) family and has a similar composition to other members of the TNF/NGF family. CD70 consists of an extracellular region, a transmembrane region, and an intracellular region. The extracellular region contains four conserved modules characteristic of the TNF/NGF family, with the module closest to the membrane being the signaling sequence for the release of CD70 molecules. The intracellular zone, on the other hand, contains a small intracellular region that activates CD27 and mediates the activation of immune cells, and participates in the regulatory process of the immune response. Abnormal expression of CD70 is associated with a variety of diseases, such as tumors, autoimmune diseases, and infectious diseases. In tumors, high expression of CD70 is associated with tumor aggressiveness, malignancy, and poor prognosis, thus becoming a potential target for tumor therapy.

Fig.1 Structure of CD70

CD70 Signaling Pathways

The main signaling pathway of CD70 is the CD27 signaling pathway. CD27 binding to CD70 activates several signaling pathways that promote the survival, proliferation, differentiation, and function of immune cells. CD70 is highly expressed in some tumors and activates the CD27 signaling pathway, which inhibits the killing effect of T cells, attenuates immune attack, and promotes tumor growth and proliferation. Studies have shown that CD70 is highly expressed in non-small cell lung cancer and positively correlates with malignancy. CD70 activation of the CD27 signaling pathway promotes multiple aspects of lung cancer cells, including proliferation, metastasis, and escape from immune surveillance, thereby promoting the development and progression of lung cancer. It has also been found that CD70 is also expressed at high levels in breast cancer patients, and both CD70 and CD27 have been detected to be closely related to multiple indicators such as tumor type, grade, and prognosis.

Moreover, the CD70/CD27 signaling pathway is involved in the immune response to various viral infections, such as hepatitis B virus and human immunodeficiency virus (HIV). Moreover, it was found that the binding of CD27 receptor and CD70 activates the IκB kinase (IKK) complex through members of the TNF receptor (TNFR)-related factor family, which allows IκB to be degraded and further activates nuclear factor κB (NF-κB) nuclear transcription factor, thus promoting the expression of inflammatory genes and the inflammatory response. But the high expression of CD70 in tumors is unique. By binding CD27, the NF-κB pathway, mitogen-activated protein kinase (MAPK) pathway, and Akt pathway can be activated to promote the proliferation, apoptosis inhibition, and metastasis of tumor cells, thus affecting the occurrence, development, and prognosis of tumors.

Clinic Status of CD70-Targeted CAR Cell Therapies

CD70 has emerged as one of the important targets in oncology therapy, and many studies are underway, including preclinical and clinical trials. Some of these studies suggest that CD70-based CAR-T cell therapy may have important efficacy and promising applications. CD70 CAR-T cell therapy can safely and effectively treat patients with CD70-positive malignant B-cell lymphoma without significant serious side effects. In addition, many studies have also found that CD70-based CAR-T cell therapy can inhibit the growth and metastasis of CD70-positive tumors in vivo, thus demonstrating significant anti-cancer effects. CD70 as a target for CAR-T cell therapy is still in the early stages of research. Currently, the main research is focused on CAR-T cell therapy for CD70-positive chemotherapy-refractory, in vivo and in vitro multiple myeloma, lung cancer, lymphoma and leukemia, and other malignancies. Its main research interests involve immunotherapy, malignancies, CAR design, and clinical trials. In particular, CAR design has undergone great innovation. The key to CAR design for CD70 CAR-T cell therapy in experiments is how to improve the affinity and specificity of CARs to enhance the therapeutic effect of CAR-T cells. A well-designed CAR structure can improve the targeting and stability of CAR-T cells while avoiding the risk of the immune system's response to CAR.

Table 1. Ongoing CD70 -Targeted CAR Cell Therapy Clinical Trials

NCT Number

Title

Status

Conditions

Sponsor/Collaborators

Phases

NCT04662294	CD 70 CAR-T for Patients With CD70 Positive Malignant Hematologic Diseases	Recruiting	Acute Myeloid Leukemia\|Non-hodgkin's Lymphoma\|Multiple Myeloma	Zhejiang University\|Yake Biotechnology Ltd.	Early Phase 1
NCT05353530	Phase I Study of IL-8 Receptor-modified CD70 CAR-T Cell Therapy in CD70+ and MGMT-unmethylated Adult Glioblastoma (IMPACT)	Not yet recruiting	Glioblastoma	University of Florida\|United States Department of Defense\|AM Rosen Foundation	Phase 1
NCT05420519	Clinical Study of CD70-targeted CAR-T Therapy for Advanced/Advanced Renal Cancer	Recruiting	Metastatic Tumor\|Renal Cell Carcinoma\|Advanced Cancer	Chongqing Precision Biotech Co., Ltd	Phase 1
NCT05518253	A Clinical Study of CD70-targeted CAR-T in the Treatment of CD70-positive Advanced/Metastatic Solid Tumors	Recruiting	Metastatic Tumor\|Advanced Solid Tumor\|Renal Cell Carcinoma\|Ovarian Cancer\|Cervix Cancer	Weijia Fang, MD\|Chongqing Precision Biotech Co., Ltd\|Zhejiang University	Phase 1
NCT05468190	A Clinical Research About CD70-positive Advanced/Metastatic Solid Tumors Treated by CD70-targeted CAR-T	Recruiting	Metastatic Tumor\|Advanced Solid Tumor\|Renal Cell Carcinoma\|Ovarian Cancer\|Cervix Cancer	Chongqing Precision Biotech Co., Ltd	Phase 1
NCT05420545	A Clinical Study of CD70-targeted CAR-T in the Treatment of CD70-positive Advanced/Metastatic Solid Tumors	Recruiting	Metastatic Tumor\|Advanced Solid Tumor\|Renal Cell Carcinoma\|Ovarian Cancer\|Cervix Cancer	Chongqing Precision Biotech Co., Ltd	Phase 1
NCT05667155	Clinical Study of Cord Blood-derived CAR NK Cells Targeting CD19/CD70 in Refractory/Relapsed B-cell Non-Hodgkin Lymphoma	Recruiting	B-cell Non Hodgkin Lymphoma	Second Affiliated Hospital, School of Medicine, Zhejiang University	Phase 1
NCT05438368	GD2/CD70 Bi-specific CAR-T Cell Therapy	Recruiting	Cancer Disease	Shenzhen Geno-Immune Medical Institute	Phase 1\|Phase 2
NCT05437341	PSMA/CD70 Bi-specific CAR-T Cell Therapy	Recruiting	Cancer Disease	Shenzhen Geno-Immune Medical Institute	Phase 1\|Phase 2
NCT02830724	Administering Peripheral Blood Lymphocytes Transduced With a CD70-Binding Chimeric Antigen Receptor to People With CD70 Expressing Cancers	Recruiting	Pancreatic Cancer\|Renal Cell Cancer\|Breast Cancer\|Melanoma\|Ovarian Cancer	National Cancer Institute (NCI)\|National Institutes of Health Clinical Center (CC)	Phase 1\|Phase 2
NCT04429438	Multi-CAR-T Cells Targeting B Cell Lymphomas	Recruiting	B Cell Lymphoma (BCL)	Shenzhen Geno-Immune Medical Institute\|The Seventh Affiliated Hospital of Sun Yat-sen University\|Shenzhen Children's Hospital	Phase 1\|Phase 2
NCT05436496	CD19/70 Bi-specific CAR-T Cell Therapy	Recruiting	B Cell Malignancies	Shenzhen Geno-Immune Medical Institute	Phase 1\|Phase 2
NCT04502446	A Safety and Efficacy Study Evaluating CTX130 in Subjects With Relapsed or Refractory T or B Cell Malignancies (COBALT-LYM)	Recruiting	T Cell Lymphoma	CRISPR Therapeutics AG\|CRISPR Therapeutics	Phase 1

References

Liu, Weifeng, et al. "Structural delineation and phase-dependent activation of the costimulatory CD27: CD70 complex." Journal of Biological Chemistry 297.4 (2021).
Crunkhorn, Sarah. "Targeting CD70 in acute myeloid leukaemia." Nature reviews. Drug discovery 19.8 (2020): 512.
Going after CD70 with CAR-T, NK Cells. Cancer Discov. 2023;13 (1):4-5.
Riether, Carsten, et al. "Targeting CD70 with cusatuzumab eliminates acute myeloid leukemia stem cells in patients treated with hypomethylating agents." Nature medicine 26.9 (2020): 1459-1467.
Balsas, Patricia, et al. "SOX11, CD70, and Treg cells configure the tumor-immune microenvironment of aggressive mantle cell lymphoma." Blood 138.22 (2021): 2202-2215.
Seyfrid, Mathieu, et al. "CD70 as an actionable immunotherapeutic target in recurrent glioblastoma and its microenvironment." Journal for Immunotherapy of Cancer 10.1 (2022).
Kumar, Sandeep, et al. "Mixed lineage kinase 3 and CD70 cooperation sensitize trastuzumab-resistant HER2+ breast cancer by ceramide-loaded nanoparticles." Proceedings of the National Academy of Sciences 119.38 (2022): e2205454119.
Benhamouda, Nadine, et al. "Plasma CD27, a Surrogate of the Intratumoral CD27–CD70 Interaction, Correlates with Immunotherapy Resistance in Renal Cell Carcinoma." Clinical Cancer Research 28.22 (2022): 4983-4994.