Anti-solid tumor "black technology" - global R&D panorama of TIL therapy

Surgery, radiotherapy and chemotherapy are the three cornerstones of cancer treatment, and immunotherapy has set off a revolution in cancer treatment.
The impaired immune function, combined with the conventional three major therapies, shows complementary advantages
.
After a lot of clinical practice, immunotherapy has shown its good application prospects in various tumor treatments, which can improve the treatment effect, prolong the survival time of patients, improve the living conditions and quality of life of tumor patients, and is expected to achieve long-term tumor-bearing survival or The goal of completely curing the tumor
.
Immune checkpoint inhibitors (PD-1/L1) Tumor vaccines (provenge, cimavax) Adoptive immune cell therapy (CAR-T): By collecting human autoimmune cells and culturing them in vitro, the number is expanded thousands of times , or increase the targeted killing function, and then return it to the patient to kill pathogens, cancer cells, and mutated cells in the blood and tissues
.
It does not directly attack cancer cells with external force, but it attacks and processes cancer cells by cultivating and processing immune cells in the patient's body, which is very different from traditional therapy
.
Using their own cells has no apparent side effects, and they can also be combined with the three main treatments to work synergistically to improve survival for cancer patients
.
Nonspecific immunomodulators
.
Normally, our immune system recognizes and eliminates infected or damaged cells as well as cancerous cells
.
This is because immune cells in our body called killer T cells recognize markers on the surface of cancer cells that become antigens
.
Adoptive cellular immunotherapy primarily exploits this natural ability and can be treated in different ways
.
1) Non-specific therapy: there is no clear immune cell target, it is a non-specific therapy that improves the overall immunity of the human body and achieves relief of tumor symptoms, such as NK cell therapy; 2) Specific therapy: has clear targets and mechanisms , which can activate or inhibit specific targets to achieve immune activation of the immune system to tumors, such as TCR and CAR therapy
.
Four types of adoptive cell therapy that have made significant research progress in the world: Tumor-infiltrating lymphocytes (TIL) therapy Engineered T cell receptor (TCR) therapy Chimeric antigen receptor (CAR) T cell therapy Natural killer (NK) cell therapy 1 Tumor-infiltrating lymphocyte (TIL) therapy Because cancer cells are very cunning, they will use some methods such as "stop" (to prevent immune cells from attacking themselves) or "blind" (to make immune cells turn a blind eye) to prevent immune cells from recognizing, Eliminate yourself - this is called "immune escape"
.
Like the current hot immune checkpoint inhibitors (PD-1, PD-L1, etc.
), they are mainly aimed at those "stop" methods.
Through drugs, the immune army can break free and attack cancer cells smoothly; CAR-T Therapy is to directly extract a part of immune cells from the human body, and use genetic engineering technology to produce "transgenic soldiers" equipped with precise positioning, so that they can target specific cancer cells, and then a large number of such soldiers are amplified and returned.
It is injected into the human body and begins to attack cancer cells
.
The TIL therapy is different from both of the above and belongs to another way (but has similarities with CAR-T)
.
Under the "stop" and "blind" methods of cancer cells, although most immune cells cannot attack cancer cells, in the immune army, there will always be some "soldiers" with particularly high IQ and strong combat effectiveness.
Overcome various insidious means of cancer cells, identify multiple targets of cancer cells, and kill tumors
.
These cells are at the heart of TIL therapy—tumor-infiltrating lymphocytes
.
TIL - is a heterogeneous lymphocyte in the tumor stroma, including T cells and NK cells
.
These cells are a "super death squad" that the body mobilizes the immune army to penetrate deep into the tumor tissue after discovering the cancer cells in the body, and has the strongest recognition, resistance and attack on the tumor
.
After reaching the inside of the tumor, it directly kills tumor cells by releasing cytotoxins
.
In addition, TIL can also regulate the body's immune function and improve the body's ability to kill tumor cells
.
Like CAR-T, TILs are a type of adoptive immunotherapy, but this is a new type of solid tumor T-cell therapy that catches up with CAR-T
.
When Professor Rosenberg used IL-2 to cure his first patient in 1985, he quickly realized that IL-2 activates a type of immune cell
.
Then the first step is to look for weapons at the "criminal scene", and naturally start experiments in "tumor infiltrating cells"
.
From 1986 when animal experiments proved that TIL was effective, to the first TIL clinical trial results published in 1988, 11 out of 20 melanoma patients had objective regression! It can be said that the great era of tumor cell therapy opened at that moment.

.
2 Engineered T Cell Receptor (TCR) Therapy Unfortunately, not all patients have tumor-recognizing T cells
.
For these patients, doctors can employ an approach called engineered T-cell receptor (TCR) therapy
.
This approach takes T cells from patients, activates and expands this subset of anti-tumor T cells, and at the same time equips T cells with new T cell receptors that allow them to recognize specific cancer antigens
.
This approach allows physicians to engineer the most appropriate targets for each patient's tumor and different types of T cells, which could personalize treatment and offer patients greater hope for remission. .
3 CAR-T: Chimeric Antigen Receptor T Cells In CAR-T cell therapy, T cells genetically engineered in vitro are very effective against some blood-borne cancers, but cannot effectively distinguish cancer cells from non-cancer cells, so although They offer important benefits, but they don't work with all forms of cancer
.
In patients with solid tumors, these T cells can lead to devastating, even fatal, side effects
.
4 Natural killer cells (natural killer cells, NK) NK cells are different from T and B cells.
They are a type of lymphocytes that can non-specifically kill tumor cells and virus-infected cells without prior sensitization
.
NK cells are the body's first line of defense against cancer cells and viruses.
They are mainly distributed in the blood, liver, spleen, bone marrow and other parts of the human body.
They have cytotoxic effects, can spontaneously kill tumor cells and pathogens, and participate in the body's anti-tumor effect.
Immune surveillance and immune response
.
TILs, CAR-T and TCR-T are the three major T-cell-based therapies, which are a new type of therapy that is completely different from traditional cell therapy
.
Among them, TILs therapy is a new type of solid tumor T cell therapy that catches up with CAR-T
.
First, TIL's immune cells come from tumor tissue, while most other cellular immunotherapies come from blood
.
It is estimated that more than 60% of immune cells isolated from tumors can recognize tumors; while less than 0.
5% of immune cells isolated from blood - this directly determines the ability of immune cells to recognize tumors
.
Second, this new type of therapy is not simply amplified and reinfused as traditional, but to identify specific mutations in patient cases
.
Then use the mutation information to find the T cells that can most effectively target these mutations, and finally extract the T cells that are specifically mutated in the cells of the patient's tumor.
These cells have the ability to accurately identify cancer cells
.
In contrast, T cells used for therapy in CAR-T and TCR-T are peripheral blood T cells transformed by gene transfection technology, which are modified rather than screened and cultured.
Therefore, the ability of accurate identification is different from that of TIL cells.
far
.
Finally, TILs have expanded in large numbers
.
After TILs cells are isolated and screened, they will be cultured with interleukin-2 to increase the chance of immune cell survival and maximize immune cell expansion, reaching tens of billions to hundreds of billions of levels, ensuring the effectiveness and activity of T cells.
Re-injected into the patient's body, which means that the body's anti-cancer "force" is greatly enhanced
.
How is TIL treatment performed? Obtain tumor tissue from the patient, send the tissue to a specialized laboratory, process the tissue, isolate tumor-infiltrating lymphocytes for in vitro culture, proliferation, collection and other cryopreservation preparations, and return it to the treatment institution.
Interleukin 2), stimulating TIL activity TIL therapy can continue to break through these tumor disease areas in the adoptive cell therapy market with mature CAR-T technology, due to its unique advantages: Like all immunotherapy options, the advantage of TIL therapy lies in improving the The immune environment suppresses tumors
.
And TIL therapy is similar to CAR-T therapy, and has the potential to enable patients to achieve clinical cure
.
TIL has stronger tumor cell targeting ability.
The main immune cells of TIL therapy are derived from the patient's tumor tissue, and have a stronger ability to recognize tumor cells than other blood-derived immune cells
.
Independent of the patient's immune process, TILs isolated from resected tumors expand to billions of cells in vitro, away from inhibitory effects, resulting in potent, highly activated cells
.
For CAR-T cells, a key factor that usually affects the success of their preparation is the quality of T cells in patients.
TIL therapy avoids this problem. .
TIL therapy is less costly and improves patient accessibility
.
For example, CAR-T/TCR-T cells need to be engineered to transfer CAR/TCR into T cells so that they have the ability to specifically target tumor cells
.
TIL therapy omits this step and only needs to screen out immune cells with specific mutations, which are then expanded in vitro and infused back into the patient
.
The cost of treatment is greatly reduced and more patients can benefit
.
Some industry experts estimate that the price of TIL therapy is about $70,000 to $80,000, and the current price of CAR-T cells is in the hundreds of thousands of dollars (Yescarta is priced at $373,000)
.
Compared with other current cancer treatments, TIL therapy is associated with fewer side effects, and most of the side effects are caused by chemotherapy prior to TIL therapy
.
The possible adverse reactions after reinfusion of TIL cells are: short-term fever, chills, and shortness of breath; other side effects include: thrombocytopenia, anemia, and low white blood cell count.
TIL therapy currently faces some challenges
.
For example, before the reinfusion, the production personnel need to expand the TIL to thousands of times in a short period of time, which is very demanding for the process
.
Second, since TIL cells have naturally homed to tumor tissue once and tend to be exhausted in the process of cell life, it is also extremely difficult for us to reverse this exhausted state and restore cell viability during in vitro expansion
.
1 Foreign companies Two US-listed companies currently developing TIL therapies: ● Iovance Biotherapeutics, Inc.
, one of the first biotech companies focused on developing TIL as a therapy, was established in 2007 and IPOed in 2010
.
Iovance First to Brief Industry, Regulators and Oncologists on the Potential of TILs for the Treatment of Solid Tumors
.
Iovance Biotherapeutics' lifileucel (LN-144) and LN-145 are the fastest-moving, unresectable or metastatic melanoma; recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), recurrent or metastatic non-small cell, respectively Phase II clinical studies in lung cancer (NSCLC) and cervical cancer
.
Among them, LN-145 has been granted breakthrough therapy by the FDA for the treatment of recurrent, metastatic or persistent cervical cancer and disease progression before and after chemotherapy
.
Over the past 5-6 years, Iovance has advanced clinical trials into Phase 2 and 3 for melanoma, cervical cancer, and head and neck cancer
.
It has already received breakthrough therapy designation from the FDA in two major cancers, melanoma and cervical cancer, and is expected to hit the market this year
.
At the SITC2020 conference in November 2020, Iovance announced the clinical trial results of its TIL cell therapy pipeline LN-145 combined with pembrolizumab (PD-1 mAb) in the treatment of advanced, recurrent or metastatic head and neck cancer.
The therapy achieved an objective response rate (ORR) of 44% and a disease control rate (DCR) of 89%
.
In addition, Iovance's TIL therapy pipeline has also shown promising results in the treatment of advanced melanoma (ORR 36%), cervical cancer (ORR 44%), and advanced NSCLC (ORR 25%) that has progressed after Opdivo treatment 's curative effect
.
Once approved, this will be the first approved adoptive cellular immunotherapy for solid tumors
.
Industry experts estimate that the price of this tailor-made immunotherapy will also be high, about 70,000 to 80,000 US dollars, which is out of reach for most domestic patients
.
● Instil Bio, Inc.
was established in 2018, IPO in 2021
.
It uses the pharma industry's "fast-track" model and builds on Iovance's success in TIL therapy
.
Through the acquisition, Instil Bio gains access to manufacturing intellectual property and process technology, as well as nearly a decade of related data
.
Instil Bio has a similar clinical pipeline to Iovance: their melanoma clinical trial is in Phase 1, and other indications (non-small cell lung cancer, head and neck cancer, cervical cancer, skin cancer) have been identified as IND-enabling
.
2 Introduction of domestic enterprises At present, TIL companies are roughly divided into two types in China: one is biased towards research and development, and the genome-level transformation of tumor-infiltrating T cells is carried out, so that the final obtained cells can respond to tumors and fight against the tumor microenvironment and lymphocyte normalization.
Nest and other aspects have been improved; the other is biased towards process development, which can expand lymphocytes with good viability on a large scale
.
1.
Beijing Cartier Medical is a representative enterprise of innovative immune cell therapy such as TIL/neoantigen in China, and has participated in a number of national, provincial and ministerial scientific research projects
.
The "super-strong TIL" therapy technology developed by the company is dedicated to conquering solid tumors, and theoretically breaks through many limitations of traditional CAR-T/TCR-T/TIL therapy.
and many other advantages
.
The clinical trial of the company's product "Super TIL" in the treatment of advanced solid tumors, chaired by several well-known PIs, including Professor Li Jin of Shanghai Oriental Hospital, is underway
.
The "super-strong TIL" immune cell therapy technology independently developed by Cartier Medical is a major upgrade of the "green out of blue" based on technologies such as TIL and CAR-T, which are currently at the forefront of the world.
"Amplification factor" and other patented technologies, the genetic modification of TIL cells has comprehensively solved the above-mentioned problems related to the heterogeneity and microenvironment of solid tumors, as well as the cell expansion process, preparation cycle and cost
.
In addition, the fourth-generation product developed by Cartier Medical, "Super-Strength cTIL", only needs to collect TIL cells in peripheral blood, breaking through the limitation that traditional TIL therapy relies on surgical tissue sampling
.
This breakthrough has made TIL therapy accessible to almost everyone, greatly expanding the applicable population
.
In February 2021, it announced the completion of the 100 million yuan Pre-B round of financing, led by Fenglin Capital
.
This financing will be used to support the completion of the IND application for the "super-strength TIL" cell therapy product of Kati Medical.
Kati Medical has previously received A+ round investment from investment institutions such as CCB Medical Growth Fund
.
2.
Jinfeng Bio was founded by entrepreneur and scientist Dr.
Yu Fuli in early 2020, aiming to develop the clinical application of TIL therapy by seamlessly integrating multi-omics/bioinformatics/artificial intelligence and cell therapy.
Treat patients with solid tumors and improve their quality of life
.
In October, it completed a series A financing of 10 million US dollars, led by Daotong Investment since its establishment
.
Jinfeng Bio has been polishing and developing its cutting-edge TIL (tumor-infiltrating lymphocyte) therapy platform, and its current "arsenal" includes neoantigen-driven TILs, single-cell multi-omics TIL scanning, and end-to-end CMC
.
The company has always adhered to the two-wheel drive of independent research and development and external cooperation, and has established close cooperation with many top research institutions in China and the United States
.
Since its establishment, Jinfeng Bio has been recognized by experts in the industry - Professor Brendan Lee, academician of the National Academy of Sciences and chair of the Department of Genetics at Baylor College of Medicine, is the angel investor and scientific advisor of Jinfeng Bio
.
Other well-known scientific advisors to the division include Professor Helen Heslop, Director of the Cell Therapy Department (CGT) at Baylor College of Medicine, and Professor Lu Shun, a medical expert
.
Dr.
Yu Fuli, founder and CEO of Jinfeng Bio, obtained his Ph.
D.
degree in molecular genetics from Baylor College of Medicine (under the tutelage of Professor Richard Gibbs, an academician of the National Academy of Sciences and a famous genomics leader), and then Dr.
Yu went to Harvard University.
Completed post-doctoral research from renowned population geneticist and paleohuman geneticist Professor David Reich)
.
Worked in the Human Genome Sequencing Center, Department of Genetics, Baylor College of Medicine, USA, participated in and led a number of major international human genome projects, including the Human Genome Haplotype Project, the Human 1000 Genomes Project, and the Human Cardiovascular Disease Project.
Received tens of millions of dollars in research funding from NIH
.
Up to now, Dr.
Yu has published more than 70 international articles, which have been cited 45,000 times, and a variety of R&D softwares under his leadership are also widely used
.
Before founding Jinfeng Bio, Dr.
Yu Fuli also served as the Chief Information Officer of Berry Genomics, mainly responsible for the overall bioinformatics analysis, product development and the application of cloud computing technology and artificial intelligence technology in genomics
.
During his tenure, Dr.
Yu successfully incubated Berry Gene's key project transformation subsidiaries: "Herui Gene Subsidiary" focusing on tumor detection, "Fujian Berry Gene Big Data Industrial Park" focusing on big data, and consumer "Circular Gene Subsidiary", which is mainly based on genetic testing,
etc.
3.
Shanghai Junsai Biotechnology Co.
, Ltd.
Junsai Biotech was established in Shanghai in July 2019.
It is a new type of solid tumor cell therapy innovation enterprise, dedicated to the development of tumor-infiltrating lymphocytes (TIL)-based solid tumor innovative therapy and "first -in-class/best-in-class" cell therapy, covering a variety of relapsed and refractory tumors
.
Core technologies such as TIL cell enrichment culture and efficient and safe non-viral vector T cell gene modification have been established.
At present, the product has entered the non-registered clinical research stage
.
Junsai Biotech completed the A round of nearly 100 million yuan in February, led by Kaitai Capital, followed by Mifang Capital, and the old shareholder Furong Investment continued to add.
Haoyue Capital served as the exclusive financial advisor for this round of financing
.
Founder/CEO/CTO "Jin Huajun, Executive Director of the Shanghai Biomedical Special Committee of the Democratic National Construction Association
.
Dr.
Jin Huajun has rich experience in cross-border employment in universities, hospitals and enterprises, and has been deeply involved in tumor immune mechanism research and cell therapy development.
Over the years, he has accumulated a lot of first-hand R&D and clinical research experience, and is proficient in the whole process of early design of new cell drugs, process and detection technology development, preclinical research, clinical research, and new drug registration and application. .
He has developed the world's first clinical-grade technology for the treatment of solid tumors by self-expressing antibody CAR-T cells, as well as the first domestic non-viral vector-based CAR-T cell new drug variety, and independently established an efficient and simple TIL cell enrichment culture technology and transgenic technology.
TIL cell therapy regimen
.
Presided over 2 major national science and technology special projects of "Major New Drug Creation", 2 National Natural Science Foundation of China, 6 other provincial and ministerial projects; applied for 80 invention patents (10 authorized); published 30 SCI papers (with the first The author or corresponding author published 20 articles); has carried out 30 clinical studies of cellular immunotherapy projects
.
4.
Grit Bio Grit Bio was established in 2019, focusing on the research and development and clinical application of innovative tumor-infiltrating lymphocyte (TIL) products for solid tumors.
TIL therapy is currently the forefront, the most competitive and industry in the field of solid tumor immunotherapy technology direction of the potential
.
The founding team of the company comes from highly professional and experienced returnee doctors.
At present, it has formed strategic partners with many top domestic hospitals
.
On December 11, 2020, it announced the completion of the 100 million RMB A round of financing, with Dr.
Liu Yarong as the founder and CEO
.
SandBio has two core advantages: First, the scientific background of the company's core team is highly complementary, and they have been deeply involved in the field of tumor immunity for many years, of which 70% have overseas experience in cell therapy industrialization, which is a very scarce talent Second, in terms of clinical operations, in just one year, more than ten tertiary hospitals have been expanded, and in-depth cooperation has been carried out, and a large number of clinical samples have been obtained to support process development
.
5.
Yuanqi Biology Yuanqi Biology (formerly known as Yuanqi Medicine) was established in 2015.
Based on pioneering and innovation, it develops affordable drugs for the unmet clinical needs of the world, and is committed to becoming the world's leading new drug for tumor immunotherapy.
the person
.
The company received an exclusive Pre-A round of nearly 100 million yuan from Qiming Venture Partners at the end of 2019, and completed a series A financing of over 200 million yuan at the end of 2020. .
After 6 years of deep cultivation, we have invested heavily to build 4 patented technology platforms based on the research and development of tumor immunotherapy drugs: Ori®Ab antibody discovery technology platform, Ori®CAR high memory and high activity CAR-T technology platform, Ori®TIL cell efficient expansion Enhanced stability and controllable culture platform, Ori®UCAR universal convenient and efficient CAR-T technology platform
.
It has broken through the efficacy bottleneck of CAR-T and other treatment of solid tumors from the aspects of target screening, tumor immune microenvironment, T cell infiltration and killing ability, etc.
, and is committed to developing innovative tumor immune cells with good efficacy, differentiation and cost.
Therapeutic drugs are constantly opening up new positions in the development wave of promoting "innovative drugs, made in China"
.
Yuanqi Ori®TIL - efficient cell expansion and culture technology platform has three technical means to effectively solve the bottleneck problems of difficult in vitro expansion of TILs cells, no specific tumor residual detection method and high preparation cost: Tumor-killing activity and purity, enhance tissue resident memory T cells (TRM) and shorten the cell culture cycle, ensuring the effectiveness of clinical applications; developed a new general detection method, which is lower than the lower limit of ordinary detection, and the T cell composition is clear.
The quality is controllable to ensure the safety of reinfusion preparations; the use of closed system production reduces the average preparation cost in terms of media, factors and other reagent consumables, equipment, personnel, and venues, and improves the affordability of clinical treatment costs
.
At present, 10 independent innovation cell drugs and bispecific antibody pipelines mainly targeting solid tumors have been formed, and 6 tumor immune cell therapy products have entered the clinical development stage
.
1.
Chinese researchers announced that they have successfully developed a new super TIL therapy
.
Different from the traditional TILs therapy in the United States, Super TIL (Super TIL, STIL) is to extract tumor-infiltrating T lymphocytes (TIL) from the patient's blood, and then transform them in vitro, so that this part of TIL cells can overcome the obstacles of the tumor microenvironment.
This new technology can simultaneously solve the three major problems of tumor identification, overcoming the microenvironment and efficient amplification, and achieve a strong tumor suppressor effect
.
According to the medical department of Global Oncologist Network, domestic TILs therapy is improved on the basis of tumor-infiltrating lymphocyte (TIL) therapy in the United States, and further genetic modification is given to enhance its ability to overcome the tumor microenvironment and increase self-amplification.
The preliminary proof-of-concept clinical study has achieved very positive efficacy and safety verification, and it has now been approved to formally conduct human clinical trials to recruit patients
.
2.
Does TIL cell therapy have corresponding druggability and quality control standards in China, or can we learn from CAR-T cell therapy? In general, TIL is a quality control standard that can refer to CAR-T
.
The release inspection of cell therapy products generally includes safety indicators and efficacy indicators
.
Safety indicators are very similar for all cell therapy products; in terms of efficacy indicators, based on the communication between FDA and IOVANCE, it can be seen that because TIL is a complex mixed cell population and has no target, neither the enterprise nor the regulatory authority has failed.
Find a clear efficacy metric to predict its ultimate efficacy
.
But as the therapy becomes popularized and developed, companies and regulators will eventually find a scientific, enforceable measure of efficacy
.
*Declaration: The statistical time ends on December 31, 2021.
Due to the limited level of the author, if there is any inadequacy in the content, please add and correct it
.
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weixin.
qq.
com/s/XK8_uTdJ6bQ9HPmmEHRq9A [2]https://m.
chunyuyisheng.
com/m/topic/493236/ [3]https:// .
com/clinical/immunotherapy-for-solid-tumors/ [4] http://care.
39.
net/a/210910/9429588.
html [5] https:// [ 6] https://zhuanlan.
zhihu.
com/p/359627865 [7] https:// [8] Official website of each company