Immune cells** are used for the first time in solid tumors** and may change the way most aggressive and advanced tumors** are used in the future.
On February 16, local time, the global anti-tumor R&D track once again ushered in a highlight moment, when the U.S. Food and Drug Administration (FDA) accelerated the approval of Lifileucel (LN-144), a product of biopharmaceutical company Iovance Biotherapeutics, for patients with advanced melanoma who have tried others, are resistant or have failed.
According to the industry, the approval of lifileucel is another milestone in the history of tumors, and may change the way most aggressive and advanced tumors are treated in the future.
As the world's first approved tumor-infiltrating lymphocyte (TIL)**, Lifileucel is also the first immune cell** approved for the fight against solid tumors. The application prospect of til** is far more than malignant melanoma, "lung cancer, head and neck cancer, colon cancer, bladder cancer.......The development and iteration of TIL** will play an important role in cancer**. Dr. Patrick Hwu, CEO of Moffitt Cancer Center in the United States, said.
In the case of all kinds of cells** have failed solid tumors**, the approval of lifileucel has played a role as a weather vane, representing a new possibility for solid tumors**. Professor Gao Quanli, director of the immunology department of Henan Provincial Cancer Hospital, told the "medical community" that he has been engaged in clinical research on TIL for a long time, "but the preparation and administration process of TIL products is still relatively complex, which also limits its accessibility in the world, including the problems in the process, and there are still many difficulties to be overcome." ”
According to the disclosure, the current list price of Lifileucel is $515,000, without taking into account Medicare and other incentives.
Save the "incurable" population
Melanoma (malignant) is a fatal form of cancer, according to statistics, about 32Of the 50,000 patients with new-onset melanoma, about 570,000 people died of the disease. About 20,000 people are diagnosed in China every year, and most of the patients are in the middle and advanced stages when they are detected. At the same time, the incidence rate is increasing year by year, with an annual growth rate of about 3%-5%.
Gao Quanli introduced to the "medical community" that early-stage melanoma can be surgically removed, and most of them can be surgically removed. If it develops to the middle and advanced stages, the mainstream mode is immunity, such as PD-1 inhibitors, or targeting. However, nearly 60% of them are ineffective due to insensitivity, drug resistance and other problems, and there is no way to do it for these patients. ”
And til** is aimed at this kind of "incurable" group of people. Similar to CAR-T**, TIL is also a one-time cell** method, which extracts immune cells from the autologous tumor, expands them in vitro and then infuses them back into the patient to achieve anti-tumor efficacy.
As early as May 30, 2023, based on the excellent clinical trial data of lifileucel, the U.S. FDA granted it priority review rights. The approval was based on the results of a Phase II clinical trial (C-144-01) in adult patients with unresectable or metastatic melanoma who had previously received immunizations such as PD-1**.
The data showed that among the 73 people who completed the prescribed dose, the objective response rate (ORR) reached 315%, or 23 people with tumors that shrank by at least 30%, of which 3 patients (4.)1%) to achieve complete remission. In 18During the 6-month follow-up period, 435% of respondents were in remission for more than one year.
Another pooled analysis of 153 patients showed a median overall survival (OS) of 13 for all patients9 months, nearly half of whom survive for more than 3 years.
That's an impressive statistic. Gao Quanli said, "The enrolled patients are all 'most advanced' patients, and even if the current hot PD-1**, the objective response rate is about 30%. After the failure of PD-1 inhibitors**, the estimated survival time of these patients is not more than 1 year. ”
However, it is worth noting that Gao Quanli said that this clinical trial is for European and American populations, and most of them are sun-damaged melanoma, that is, the tumor grows on the surface of the first tissue. According to statistics, the proportion of ** type melanoma in the United States has reached 912%。
Among the melanoma patients in China, there are less than 1 3 types of **, and most of the others are mucosal and acral melanoma. Previous studies have shown that patients with mucosal and acral forms have poor susceptibility to immunity**. Gao Quanli said that whether TIL** can replicate the same results in such patients is still lacking data and remains to be seen.
Overall, the outlook for TIL** is exciting. In addition to melanoma, related products have previously disclosed dazzling data in advanced lung cancer, breast cancer, cervical cancer, etc. Gao Quanli said, "The research and development of til** has lasted for decades, and the first product has finally been approved, and the efficacy is still so 'magical', which is an important reason why lifileucel can cause a sensation in the industry." ”
36 years to sharpen a sword
If the emergence of CAR-T has changed the pattern of hematologic tumors, then TIL** has filled the gap in the field of solid tumors with immune cells.
The difference between TIL and CAR-T is that CAR-T extracts immune T cells from the blood of cancer patients, which are then genetically engineered to recognize and attack cancer cells, and then expanded in vitro and infused back to the patient.
Til**, on the other hand, directly isolates infiltrating lymphocytes in the patient's tumor without modification, and this type of cell population itself contains a large number of natural T cells targeting tumor-specific mutant antigens, with many anti-tumor targets and stronger estimated lethality.
In 1988, Dr. Steven Rosenberg, the inventor of Til** and the National Cancer Institute, and his team first reported on patients with melanoma in the New England Journal of Medicine, and disclosed preliminary positive results. TIL** has then entered the academic field of vision, and has successively shown excellent clinical trial data in different cancer types.
But after nearly 36 years, the first product came out, down to the reason, Gao Quanli's analysis of the "medical community", on the one hand, the initial academic community was not optimistic about the prospect of tumor immunity, in addition, Til** needs to obtain the patient's tumor tissue, especially for non-body cancer, "It is conceivable that a terminal cancer patient, you and he said that to do clinical research, you have to open a knife again to cut a piece of tumor tissue, most people are difficult to accept this test method, compared with other **, Til** clinical trials are more difficult to carry out." ”
Even if the patient's tumor tissue is successfully obtained, the preparation time of TIL is relatively long, and about one-third of patients cannot successfully culture TIL, and the high cost of the trial and the expected high price have become the biggest obstacle limiting its wide application in clinical practice.
Until the PD-1 inhibitor in 2014 and CAR-T in 2017, the discipline of tumor immunology developed rapidly, and the US FDA successively approved a number of tumor immunity**, which once again ignited the attention of the academic community and industry to immune cells**.
In 2016, TIL** ushered in a highlight moment, in the TIL** clinical trial led by Professor Rosenberg, all 7 metastatic lesions in the lungs of a patient with advanced KRAS-mutant colorectal cancer regressed, which shocked the tumor community.
In 2017, the Annals of Oncology reported that 6 patients with advanced metastatic ovarian cancer had lesions shrinking after TIL**; In 2019, the Journal of Clinical Oncology reported that the objective response rate of TIL** was 44% in 27 patients with ** or metastatic cervical cancer, 1 had a complete response, and 11 had long-term efficacy. In 2021, Nature Medicine reported that 11 of 13 patients with advanced non-small cell lung cancer (NSCLC) had a reduced tumor burden, and 2 achieved complete remission after 1 and a half years.
At present, there are at least 75 TIL** R&D pipelines in the world. But despite the succession, it may be years before the industry is approved for other types of cancer.
Re-infusing billions of cells back into the body is not entirely risk-free. William Dahut, chief scientist at the American Cancer Society, said in a recent interview that "the human immune system may suffer from a cytokine storm, which can lead to flu-like symptoms, low blood pressure and organ damage." ”
Gao Quanli added to the "medical community" that under normal circumstances, after TIL is infused back into the human body, doctors need to adjuvant chemotherapy and carry out interleukin-2 concomitant medication, "The purpose is to suppress the human immune system and promote the expansion of TIL in vivo, which may bring certain hidden dangers." "According to the FDA, common *** associated with lifileucel include abnormal heart rate, fluid buildup, rash, hair loss, and shortness of breath.
In addition, the current effect of TIL is mixed, in the same batch of clinical trial enrollment, some people have excellent efficacy, and some patients do not respond, "This may be because the TIL extracted from the tumor of a certain type of patient itself cannot kill cancer cells, and it may also be affected by the differences in the microenvironment of individual tumors." Further research is needed on the relevant mechanisms. Gao Quanli said.
The bigger challenge is that it is difficult to scale production. At present, til** needs to be customized individually, involving multiple processes, and the preparation cycle of a single person is more than one month, during which there are still various uncertain factors. Until this issue is resolved, the cost and selling price of TIL will remain high.
Given the unmet clinical needs of our advanced melanoma patient population, we are proud to offer them personalized, one-off** options. Following the approval of Lifileucel, Iovance's interim chief executive officer, Frederick Vogt, said, "We are also advancing research and development to meet more medical needs and enable this new type of cell** to benefit more types of cancer patients." ”
How is the local team doing?
According to incomplete statistics, including Carti Medical, Junsai Biotechnology, Gravel Biotechnology, Jinfeng Biotechnology, Cellular Biotechnology, etc., many local companies have also successively laid out the TIL** track, and have built independent innovation platforms in immune cell population screening, in vitro in vivo amplification, genetic modification, vector design and other links, in order to further improve the stability, effectiveness and accessibility of TIL**. So far, 6 local TIL products have been approved by the State Food and Drug Administration of China.
Gao Quanli's team has also further developed liquid TIL (L-TIL) and cooperated with relevant industry parties to promote research and development. According to reports, among the more than 30 advanced cancer patients with a cumulative **, a kidney cancer patient with brain metastases had a brain tumor that shrank significantly after **; Two patients with advanced melanoma achieved objective remission, and one of them has survived without tumor for nearly five years and achieved clinical **.
According to previous literature, there is also a fraction of TIL released from tumor tissue in the blood. Without surgery, we directly extract and amplify the preparation of TIL from the patient's peripheral blood, which solves the limitation of the difficulty of traditional TIL** collection. Gao Quanli said. After the release of the relevant study, Professor Ladle of Johns Hopkins University in the United States commented, "Although there is still a need to further prove the efficacy of L-TIL**, this technology greatly solves a major obstacle to the clinical application of TIL**." ”
According to the research report, since the launch of the first CAR-T** in 2017, the global market for tumor immune cells** products has grown rapidly, with an average annual growth rate of 87 from 2018 to 20217%, and the market size is expected to reach $35.9 billion by 2028. In China, the market for tumor immune cells** is expected to grow to 94.5 billion yuan in 2030.
More than 10 years ago, the expected survival time for patients with malignant melanoma was an average of 1 year. With the advent of immunization**, the current 5-year survival rate has exceeded 50%, which is an extremely remarkable achievement. Gao Quanli said. In addition, antibody-drug conjugates (ADCs), tumor neoantigen vaccines, and radionuclide-targeted** (RDC) ......Tumor innovation has blossomed in many places, and good news has been frequent, especially for breast cancer, and there has been optimism in the industry that breast cancer is about to enter the "era of chronic diseases".
For the local scientific research force, Gao Quanli said that the local team is catching up quickly in the technical link, "We have a strong learning ability, and the country has also encouraged biomedical innovation in recent years." But in the end, in order to achieve 'corner overtaking', it is not just limited to imitation, for example, for TIL**, it is necessary to precipitate and make breakthroughs in the field of basic disciplines including immunology, in order to truly make a 'revolutionary' product. ”
As for the "sky-high price" of innovative drugs that frequently arouse heated discussions, Gao Quanli believes that in addition to continuously promoting research in the field of industry, education and research, and further reducing costs by improving various technical means, various supporting policies, including medical insurance, are also crucial, "Clinical innovation is not only a scientific breakthrough, sometimes a policy breakthrough is more important." Industry-university-research and policies need to work closely together to make an integrated top-level design, so that the frontier can ultimately benefit most patients. Gao Quanli said.
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