What is the research progress of CAR-T therapy for lung cancer?

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What is the research progress of CAR-T therapy for lung cancer?

What is the research progress of cellular immune CAR-T therapy for lung cancer? Can there be breakthroughs in the future?

CAR-T, short for Chimeric Antigen Receptor T-Cell Therapy, is a new type of tumor immunotherapy. It extracts T cells from the patient’s own immune system, cultures and transforms them in vitro, equips these T cells with special molecules so that they can recognize and attack specific cancer cells, and then injects the transformed T cells back into the patient’s body.

The immune response of these T cells against cancer cells destroys cancer cells.

In 2017, the U.S. FDA approved the first immune cell therapy-CAR-T (CTL019, Kymriah) targeting CD19, which was officially launched, setting off a new frontier of medical innovation. It has become difficult to attack cancer by reorganizing patients’ own cells. A new turning point in the treatment of diseases has opened the prelude to immune cell therapy. Subsequent drugs have been launched on the market.

At present, CAR-T therapy has been relatively successful in the study of hematological malignancies, while successful studies on solid tumors (such as lung cancer) are limited. According to the registration on Clinical Trial.gov, as far as CAR-T is concerned, more than 500 related clinical trials have been carried out globally, most of which are for hematological malignancies. Solid tumor research only accounts for about 1/4 of them. Most of them focus on non-small cell lung cancer (NSCLC).

Research progress of CAR-T in non-small cell lung cancer (NSCLC)

Research status of targeted antigen EGFR

EGFR is a common driver gene for NSCLC and is related to tumor proliferation, new blood vessel formation and metastasis. Recombinant anti-EGFR CAR-T cells have specific cytolytic activity against EGFR-positive tumor cells, thereby accurately destroying tumor cells.

Beijing 301 Hospital took the lead in developing CAR-T therapy in China, with remarkable results. Professor Han Weidong once reported using EGFR as the target CAR-T to treat patients with advanced and refractory NSCLC with strong EGFR expression (EGFR expression exceeding 50%).

CAR-T cells are produced from peripheral blood and stimulated in vitro before treatment 10-13 days. The results of the study showed that the curative effect of 11 patients was evaluable, the tumors of 2 patients were significantly reduced, and the disease of 5 patients was stable. Patients can tolerate anti-EGFR CAR-T cell perfusion for 3 to 5 days without serious toxicity.

In the phase I clinical trial conducted by Sun Yat-sen University, the efficacy and safety of CXC chemokine receptor (CXCR) type 5 modified anti-EGFR CAR-T cells in the treatment of advanced NSCLC EGFR-positive patients are being evaluated (NCT04153799).

Current Status of Targeted Antigen CEA Research

CEA is a common tumor marker for tumors of the digestive tract. CEA CAR-T cells constructed with CEA as a target can improve the anti-tumor immunity of CEA-positive rectal cancer cells.

The clinical phase I trial found that in the treatment of CEA-positive, relapsed, refractory, and liver-lung metastasis patients with colorectal cancer through intravenous infusion of CEA CAR-T cells, 7 out of 10 patients were in remission, and 2 were in remission.

Stable for more than 30 weeks, 2 cases of imaging diagnosis showed that the tumor volume was reduced, most of the patients’ serum CEA levels were significantly reduced and remained at a low level for a long time, and CAR-T cells were found to proliferate and persist in the patients’ peripheral blood, which indicates CEA CAR-T cells are effective in treating colorectal cancer.

Research progress of targeting PD-L1

In recent years, PD-1 antibodies have achieved satisfactory results in in vitro cell co-culture models, in vivo animal models, and clinical trials for the treatment of various cancers including NSCLC, and their clinical applications have become more and more extensive.

In the field of CAR-T therapy, a study published in Oncogenesis on August 13, 2020 proved that PD-L1 CAR-T cells have anti-solid tumor activity in vitro, not only the high expression of PD-L1 in mice NSCLC xenograft tumors also achieved prolonged remission. This discovery provides preclinical evidence to support CAR-T cells targeting PD-L1 to treat NSCLC and other solid malignancies.

In the clinical stage, autologous CAR-T cells targeting PD-L1 and CD80/CD86 are used in a phase I early study (NCT03060343) to treat relapsed or refractory NSCLC to determine safety, tolerability and implantation potential . Another phase I clinical study (NCT03330834) is also testing the safety and effectiveness of anti-PD-L1 CAR-T cell therapy in patients with advanced PD-L1 positive NSCLC.

Other targeted antigens

The most common CAR-T targeting antigens for NSCLC include EGFR, CEA, PD-L1, CD80/CD86, etc. Other CAR-T cell targeting antigens include ganglioside GD2, melanoma-associated antigen (MAGE)-A1, MAGE-A4 and Lewis-Y antigens, etc.

Research progress of CAR-T in small cell lung cancer (SCLC)

Previously reported in the literature, about 80% of small cell lung cancer (SCLC) patients showed positive expression of DLL3 in tumor tissues, but almost no expression in normal tissues.

Research on AMG 119 targeted therapy for SCLC is ongoing. Different from other CAR-T therapies, the target of T cells after AMG 119 “modified” is delta-like protein 3 (DLL3). Currently, the AMG 119 trial is expected to recruit 41 SCLC patients, who must have used at least one platinum-containing chemotherapy regimen after disease progression or recurrence. There are also some drugs under study for this target, such as rovalpituzumab tesirine (referred to as Rova-T).

In addition, there is also a phase I trial of AMG 757 in the treatment of SCLC, and the target is also DLL3. The results of the phase I study of AMG 757 in the treatment of relapsed SCLC reported by the ELCC in 2021 showed that: nearly 50 of 52 cases of relapsed SCLC % Of patients have received PD-1/PD-L1 inhibitor treatment, 7 patients still achieved partial remission (PR) after AMG 757 treatment, the objective remission rate (ORR) reached 14%, and the disease control rate (DCR) reached 37%.

Among the 7 patients with PR confirmed, the median time to disease remission was 1.8 months. Among patients with a median follow-up of 11.5 months, 83% had a duration of remission (DoR) greater than 6 months. Further analysis showed that patients with high DLL3 expression had a higher ORR, reaching 38%.

In terms of safety, the incidence of treatment-related adverse events (TRAE) ≥3 was 23%, the common TRAE cytokine release syndrome (CRS) was 44%, and the incidence of ≥3 CRS was 2%. The incidence of grade 4 AEs was 8%, including pneumonia (n = 1) and lymphopenia (n = 3); one patient died of pneumonia. CRS has nothing to do with discontinuation or death of the patient.

Summary and outlook

As a new strategy for the treatment of lung cancer, CAR-T cell therapy has made considerable progress, and related clinical studies are also being carried out. Although it has certain side effects and potential risks, compared with conventional treatments, it has stronger target binding ability and longer duration of efficacy in the body. It may provide more beneficial help for the treatment of lung cancer in the future.

references

1. Takamori S, Toyokawa G, Takada K, et al. Combination Therapy of Radiotherapy and Anti-PD-1/PD-L1 Treatment in Non-Small-cell Lung Cancer: A Mini-review. Clinical Lung Cancer, 2017, 19 (1).

2. Anti-EGFR chimeric antigen receptor-modifed T cells in metastatic pancreatic carcinoma: a phase I clinical trial. Cytotherapy, 2020.