CAR T-Cell Therapy for breast cancer
CAR T-cell therapy has dramatically changed the treatment paradigm of many cancers, especially hematologic malignancies. Its application in solid tumors, such as breast cancer, is an area of active research focusing on identifying and targeting specific tumor-associated antigens (TAAs) to enhance therapeutic efficacy. This blog discusses the progress in CAR T-cell therapy for breast cancer, emphasizing key target markers and highlighting pertinent studies from the USA and China.
Breast cancer
One of the most common cancers in the world is breast cancer, affecting millions of women, and very occasionally, men. It rises within the tissue of the breast-often within milk ducts or lobules. If left undiscovered at the early stages, it may reach other parts of the body and cause havoc there. Some risk factors are identified as follows: genetic predispositions, for instance, mutations to BRCA1 and BRCA2, hormonal influences, lifestyle factors, and environmental exposures.
Breast cancer is divided into several different subtypes, including hormone receptor-positive (ER/PR+), HER2-positive, and triple-negative breast cancer (TNBC). TNBC is the most aggressive form where the cancer cell lines lack estrogen, progesterone, and HER2 receptors, which makes the treatment challenging using conventional therapies.
Early detection through mammography, self-examinations, and clinical screenings significantly improves survival rates. The treatment of breast cancer is based on the stage and type of cancer diagnosed and may involve surgery, chemotherapy, radiation therapy, targeted therapy, and immunotherapy. Recent progressions, such as CAR T-cell therapy, have been found to be hopeful for difficult-to-treat cases.
Raising awareness, promoting research, and improving access to early diagnosis and treatment remain key strategies in the fight against breast cancer, ultimately improving patient outcomes and survival rates worldwide.
CAR T Cell therapy
It is one of the groundbreaking forms of immunotherapy that puts to bear the power of a person’s own immune system against cancer. This treatment involves making T cells carry a synthetic receptor known as CAR that specifically makes them recognize tumor-specific antigens expressed by cancer cells, and on infusing them back into the body, these engineered T cells can recognize and destroy cancer cells with remarkable precision.
CAR T-cell therapy has greatly succeeded in hematologic malignancies, including leukemia and lymphoma. The same cannot be said for its use in solid malignancies such as breast and lung cancer. Such is mainly attributed to heterogeneity of tumors, the immunosuppressive nature of the tumor microenvironment, and lack of targetable antigens. Many researchers are pursuing CAR T-cell therapy in the treatment of breast cancer with attention to HER2, MUC1, and FRα for specificity and potency.
Though promising, CAR T-cell therapy comes with potential side effects, including cytokine release syndrome (CRS) and neurotoxicity. Studies are underway to improve safety and efficacy, including the development of bispecific CARs and armored CAR T cells. As the clinical trials advance, CAR T-cell therapy promises to revolutionize cancer treatment and provide hope to patients with aggressive or treatment-resistant cancers.
Pic: Working of CAR T Cell therapy
CAR T Target Markers in Breast Cancer
Effective CAR T-cell therapy hinges on selecting appropriate target antigens that are predominantly expressed on tumor cells, minimizing potential damage to normal tissues. Notable TAAs in breast cancer include:
Folate Receptor Alpha (FRα): FRα is overexpressed in various epithelial cancers, including breast cancer, and is associated with poor clinical outcomes. Its expression is notably higher in triple-negative breast cancer (TNBC), making it a promising target for CAR T-cell therapy.
Receptor Tyrosine Kinases (RTKs):
- AXL: Part of the TAM family of RTKs, AXL is implicated in tumor cell survival, metastasis, and chemoresistance. Overexpression of AXL is a strong predictor of poor survival and clinical outcomes in breast cancer patients. Check the full article below.
- HER2: Approximately 20-30% of breast cancers exhibit HER2 overexpression, correlating with aggressive disease and poor prognosis. HER2-targeted therapies have been pivotal in managing such cases.
- ROR1: This RTK is implicated in tumor progression and metastasis. In breast cancer, increased ROR1 expression induces expression of ATP-dependent drug efflux pumps (ABCB1), resulting in chemotherapy resistance and tumor recurrence.
- HER2: Approximately 20-30% of breast cancers exhibit HER2 overexpression, correlating with aggressive disease and poor prognosis. HER2-targeted therapies have been pivotal in managing such cases.
- AXL: Part of the TAM family of RTKs, AXL is implicated in tumor cell survival, metastasis, and chemoresistance. Overexpression of AXL is a strong predictor of poor survival and clinical outcomes in breast cancer patients. Check the full article below.
NKG2D Ligands: These stress-induced ligands are expressed on tumor cells and recognized by the NKG2D receptor on natural killer (NK) cells. Targeting NKG2D ligands can enhance the immune response against tumors.
Mucin 1 (MUC1): A transmembrane glycoprotein, MUC1 is overexpressed and aberrantly glycosylated in many breast cancers, including TNBC. This altered form, known as tMUC1, is a viable target for CAR T-cell therapy.
Integrin Alpha V Beta 3 (αvβ3): This integrin plays a role in tumor cell migration, invasion, and survival. Its expression is observed in various malignancies, including TNBC, making it a potential target for CAR T-cell therapy.
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CAR T-Cell Therapy in Triple-Negative Breast Cancer (TNBC)
TNBC is a particularly aggressive subtype of breast cancer lacking estrogen, progesterone, and HER2 receptors, limiting treatment options. Several studies have explored CAR T-cell therapies targeting specific antigens in TNBC:
Folate Receptor Alpha (FRα): FRα-specific CAR T cells have demonstrated potent and specific killing of TNBC cells expressing moderate levels of FRα in vitro and significantly inhibited tumor outgrowth in mouse models. However, the antitumor activity was more pronounced in tumors with higher FRα expression, suggesting the importance of patient selection based on antigen levels.
AXL: CAR T cells targeting AXL have shown significant antitumor effects in TNBC models. In vitro studies demonstrated increased cytokine release and direct cancer cell lysis, while in vivo models exhibited inhibited tumor growth.
MUC1: CAR T cells targeting the tumor-specific form of MUC1 (tMUC1) have exhibited significant cytotoxicity against TNBC cells. In preclinical models, these CAR T cells reduced tumor growth and demonstrated high therapeutic potential with minimal damage to normal tissues.
Clinical Studies and Trials
Several clinical trials are underway to evaluate the safety and efficacy of CAR T-cell therapies targeting these antigens in breast cancer:
MUC1-Targeted CAR T Cells: A Phase I/II trial is assessing autologous CAR T cells targeting the MUC1 transmembrane cleavage product (MUC1*) in patients with metastatic breast cancer. The study aims to determine safety, optimal dosing, and preliminary efficacy.
FRα-Targeted CAR T Cells: Preclinical studies have demonstrated that FRα-specific CAR T cells can effectively target TNBC cells expressing FRα. These findings suggest potential for clinical application, particularly in patients with high FRα-expressing tumors.
Advancements in China
China has been at the forefront of CAR T-cell research, with several studies focusing on breast cancer:
TROP2-Targeted CAR T Cells: TROP2 is overexpressed in TNBC and plays a role in tumor growth and metastasis. Chinese researchers have developed TROP2-specific CAR T cells that demonstrated potent cytotoxicity against TNBC cell lines in vitro and significant antitumor activity in mouse models.
Bispecific CAR T Cells: To address tumor heterogeneity, studies have explored CARs targeting multiple antigens simultaneously. For instance, a bispecific CAR targeting both CD70 and B7H3 exhibited enhanced efficacy against various cancers, including breast cancer, in preclinical
Conclusion
CAR T-cell therapy is a promising frontier for breast cancer treatment, especially for aggressive subtypes, including triple-negative breast cancer. Using genetically engineered T-cells, targeted immunotherapy is being developed against the said tumor-associated antigens; FRα, HER2, AXL, ROR1, NKG2D ligands, MUC1, and Integrin Alpha V Beta 3. These have offered new hopes to patients with said conventional management uses up all avenues to treatment.
Although CAR T-cell therapy has already revolutionized the management of hematologic malignancies, its application to solid tumors is still challenging because of the tumor microenvironment, antigen heterogeneity, and potential toxicities. However, preclinical and clinical studies underway in the U.S. and China, including trials conducted in leading Chinese hospitals, are now making significant headway in these challenges.
The integration of dual-targeting CAR T-cells, combination therapies, and next-generation CAR designs is going to open the avenues for improved efficacy and reduced off-target effects with continued research. It may just be the innovation in the form of these immunotherapies that shape the future of breast cancer treatment and brings us closer to a world where even the most aggressive forms of breast cancer can be managed or cured.