Magic TCR-T cell therapy: 72% of tumor lesions disappeared

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Magic TCR-T cell therapy: 72% of tumor lesions disappeared

NEJM: One injection of 16.2 billion immune cells, 72% of tumor lesions disappeared, magical TCR-T cell therapy

Recently, a new type of immunotherapy TCR-T therapy published on NEJM caused a sensation! The original title is “Neoantigen T-Cell Receptor Gene Therapy in Pancreatic Cancer”.

One month after a patient with advanced metastatic pancreatic cancer (KRAS G12D mutation) received a one-time infusion of 16.2 billion immune cells, the metastatic lesions in the patient’s body began to subside; 6 months later, after evaluation, the patient’s lesions disappeared by 72% !

It appeared to be successful in halting the progression of the patient’s advanced pancreatic cancer.

Magic TCR-T cell therapy: 72% of tumor lesions disappeared

The reason why this study caused a sensation in the medical world is that about 90% of pancreatic cancers currently have KRAS mutations, and the most common subtype is KRAS G12D, accounting for 41%! For this huge patient population with a specific target, no targeted drug has been approved so far!

Now, researchers have specifically developed TCR-T therapy targeting KRAS G12D, which will bring new hope of curing most patients with pancreatic cancer.

The world’s first advanced pancreatic cancer patient benefited

This is a 72-year-old female patient (CRI-4483), who is also the first advanced pancreatic cancer patient in the world to benefit.

In 2018, the 67-year-old female patient was diagnosed with pancreatic cancer, followed by four cycles of FOLFIRINOX neoadjuvant therapy (fluorouracil, leucovorin, irinotecan and oxaliplatin), followed by pylorus-preserving patency Sexual Whipple resection, which removed a poorly differentiated adenocarcinoma (4.5 cm in maximum dimension) with negative margins and 2 lymphatic involvement.

Post-treatment disease stage IIB, the patient received an additional four cycles of adjuvant FOLFIRINOX followed by adjuvant chemoradiotherapy at a dose of 50.4 Gy concurrently with capecitabine.

After completion of treatment, she was in remission and showed no tumor re-metastasis.

In 2019, the cancer began to spread again, and doctors confirmed the presence of lung metastases through a fine-needle aspiration of an enlarged nodule in the right lower lobe of the lung.

In 2020, the patient participated in the clinical trial of tumor-infiltrating lymphocyte therapy at the University of Pittsburgh Medical Center (registration number, NCT03935893), and applied to participate in this brand-new immune cell therapy-TILs treatment, but lung metastasis was observed within 6 months Tumor growth, a failure.

In desperation, waiting to die, the patient saw a clinical trial of a single-patient new immunotherapy approved by the FDA in May 2021 -TCR-T Investigational New Drug Application.

With the mentality of giving it a try, the female patient participated.

In June 2021, the patient officially underwent clinical trials. The researchers first extracted the patient’s T cells, carried out genetic modification in vitro, and prepared a large number of TCR-T cells that can specifically recognize the KRAS G12D mutant cancer cells in the patient, and then injected this T cell that can accurately kill cancer cells. The cells are infused back into the patient.

Patients were treated with a conditioning regimen of tocilizumab (600 mg, intravenously) and cyclophosphamide (30 mg/kg body weight per day, intravenously, for 2 days) starting 5 days before cell infusion. Eighteen hours after the cell infusion, the patient started receiving high-dose interleukin (600,000 IU/kg intravenously every 8 hours for a total of 5 doses).

After 1 month of treatment, the patient’s metastatic lesions began to subside; 6 months later, after evaluation, the patient’s lesions disappeared by 72%!

Magic TCR-T cell therapy: 72% of tumor lesions disappeared

Figure 1: Preparation of KRAS G12D engineered T cells for a patient with bowel cancer, and contrast-enhanced computed tomography scans of the patient’s chest before infusion and at days 85 and 176 after infusion

Not only that, but in the journal “Nature Medicine” in January 2023, the world-renowned cancer center – MD Anderson Cancer Center in the United States announced the latest data of the phase 1 trial of afami-cel, a new type of adoptive T cell therapy. The original title is “Autologous T cell therapy for MAGE-A4+ solid cancers in HLA-A*02+ patients: a phase 1 trial”

Experiments were conducted in patients with 9 types of solid tumors, including lung cancer, gastroesophageal junction cancer, ovarian cancer, and head and neck cancer.

The results of the study show that the clinically extremely difficult-to-treat advanced patients who have failed multiple treatments can achieve long-term remission for various cancer patients after TCR-T treatment, and there is a chance that the patient’s tumor will disappear completely.

This means that the use of autoimmune cells to kill tumors will gradually become a reality!

What is the magic of TCR-T therapy? What is stronger than CAR-T?

TCR-T technology, also known as T cell receptor (TCR) chimeric T cell technology, also known as affinity-enhanced TCR” technology, is to enhance the recognition affinity of T cells through genetic modification, so that your own Killer T cells have a stronger ability to recognize and achieve the effect of treating tumors.

Magic TCR-T cell therapy: 72% of tumor lesions disappeared

Figure 2: TCR-preparation process

Generally, T cells are obtained from patients, and T cells are equipped with new T cell receptors, so that they can target specific cancer antigens. T cells are engineered to select the most appropriate target to personalize therapy.

The frequent good news of TCR-T cell therapy also makes people have to associate TCR-T cell therapy with the very hot CAR-T cell therapy.

Although both CAR-T cell therapy and TCR-T cell therapy are modified on T cells, their utilization principles are different.

The method of CAR-T cell therapy is to install a “CAR navigation” on T cells, and through the way of antibody-antigen recognition, T cells can be accurately brought to the designated killing target, thereby stimulating the immune function of T cells.

The way of TCR-T cell therapy is to directly modify the “probe” TCR (T cell antigen receptor) that T cells bind to tumor antigens, so as to strengthen the specific recognition process of T cells against tumor cells.
In general, CAR-T cell therapy and TCR-T cell therapy have different directions of action due to their different working principles.

CAR-T cell therapy acts by recognizing tumor surface antigens in a more direct manner and does not require the process of antigen presentation, which makes CAR-T therapy more suitable for hematological tumors with a higher degree of surface antigen exposure.

Due to the less exposed antigens on the surface of solid tumors and the presence of tumor microenvironment, it is difficult for CAR-T cell therapy to enter the interior of solid tumors to kill cancer cells. TCR-T cell therapy can recognize antigens inside the tumor, so it is more effective in the field of solid tumors.

Currently, the FDA has approved a bispecific gp100 peptide-HLA-directed CD3 T cell engager for HLA-A*02:01 positive unresectable or metastatic uveal melanoma, which is the first in the world to be approved TCR-T therapy for solid tumors, which means that TCR-T therapy has officially begun to land.

References:
https://www.nature.com/articles/s41591-022-02128-z
https://www-nejm-org.soton.idm.oclc.org/doi/full/10.1056%2FNEJMoa2119662

Magic TCR-T cell therapy: 72% of tumor lesions disappeared

(source:internet, reference only)

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