Li Wei Reviews . . . TCR-T cell therapy, three major obstacles to be broken.

The rise of CAR-T cell immunotherapy is a major advance in cancer treatment.
These therapies play an anti-cancer role by genetically adapting patient/provider T cells in vitro to express chime antigens (CAR) that identify specific antigens in cancer cells, and then amplification and re-transmission to the patient.
these CARS allow T-cells to destroy cancer cells by identifying targets on their surfaces.
, however, because many cancer targets are located in cancer cells and are beyond the range of CAR protein exposure, CAR-T cell therapy has limitations for solid tumors.
in the past few months, some European start-ups have made progress in T cell receptor (T cell receptor, TCR) T-cell immunotherapy.
TCR-T cells may be better at "killing" solid tumors than CAR-T cells.
this is because TCR, a genetically modified protein on TCR-T cells, can identify targets hidden in cancer cells by scanning the surface of cells for a protein called human lewd cell antigen (HLA).
August 6th T-knife, a Berlin-based biotech company, brought TCR-T cell therapy into the spotlight with a 66 million euro round of financing led by Versant Ventures and RA Capital Management.
TCR-T cell therapy developers adjusted existing human TCR, T-knife obtained TCR for "hunting" cancer from mice.
the company genetically modified mice to produce all-humanized TCR and injected them with human tumor antigens.
then the mice's immune system responded to cancer antigens, producing a variety of TCR.
the mice's immune system to find the best TCR for cancer, T-knife expressed it into the patient's T-cells, resulting in cell therapy. elisa Kieback, ceo and co-founder of
T-knife, said: "The mice's immune systems are resistant to human tumor antigens and are treated as viruses or pathogens.
, when immune mice with human tumor antigens, a strong immune response can be produced in mice.
," Kieback said, the company's mouse-sourced TCR is stronger and more specific to cancer antigens than existing TCR-T cell therapy biotechnologies such as Immatics and Adaptimmune.
mice to choose the best TCR through a very natural in vivo selection mechanism, which means they are less likely to have off-target effects," she said.
, T-knife has begun clinical development of myeloma treatment and plans to launch a solid tumor trial by the end of 2021.
disadvantage of universal TCR-T cell therapy based on genetically modified patients' own T-cells is that the process is complex and costly and must be tailored to each patient.
to solve this problem, some European start-ups have been developing generic TCR-T cell therapy, which uses immune cells from the provider to reduce the cost of treatment.
photo source: Zelluna Immunotherapy, a Norwegian biopharmaceutical company, raised 7.5 million euros in equity financing and grants in June.
the company's goal is to develop a TCR-NK cell therapy based on anti-cancer immune cells, natural killer cells (NK).
Zelluna believes these cells are well suited for "universal" therapies because they attack patients' healthy tissue at a lower risk than T-cells and kill cancer cells faster.
another generic TCR-T cell therapy is being developed at Gedeta, a Dutch biotech company.
the company is working with U.S. company Kite Pharma to develop a new cancer immunotherapy based on the T-cell receptor.
TCR of gamma T cells is better able to recognize pressure signals on cancer cells than more common alpha beta T cells. marco Londei,
's new chief executive, said, "Gadeta's platform combines the key properties of alpha beta T cells, such as high proliferation and memory capabilities, as well as the anti-cancer specificity and activity of selected gamma receptors.
this new T-cell platform is ideal for possible isotrophy 'universal'.
" Gadeta is currently preparing to enter a Phase I trial for multiple myeloma treatment.
Scottish start-up TC Biopharm has also shown the future of its generic cancer cell immunotherapy.
the company collects gamma T cells from young, healthy donors and makes them produce CAR proteins similar to CAR-T cell therapy.
, however, this is not an ordinary CAR-T cell therapy.
TC BioPharm also uses TCR as a safety measure to avoid damaging healthy cells that happen to show cancer targets.
car proteins to identify tumor targets on the surface of cells, but terabyte tCR only allows cell therapy to kill cells that have cancer stress signals.
may make it safer than current CAR-T cell therapy.
TC BioPharm last year launched a Phase I clinical trial for acute myeloid leukemia.
said: "The trial is going well.
all eligible patients showed significant responses to treatment, reducing the burden on the tumor.
hope that this treatment will be available around 2021-2022.
" expanded treatment range Although TCR-T cell therapy can target more types of cancer than CAR-T cell therapy, they still tend to target specific types of cancer and are ineffective against other cancers.
are often more heterogenetic than originally thought," said CMO Kai Pinkernell of Medigene, a German biotech company.
", can such a treatment target more than one cancer? In June, Medigene launched a Phase I clinical trial of a candidate for TCR-T cell therapy for multiple blood cancers.
therapy is designed to target the antigen HA-1, which is common to these blood cancers and is expressed only on cells of the hematosis system.
trial is being tested in patients who recently received a bone marrow stem cell transplant but have a recurrence of blood cancer.
another TCR-T cell therapy company aims to further expand the scope of treatment.
In January, London-based Ervaxx, recently renamed Enara Bio, signed a partnership agreement with Cardiff University to overcome a common limitation of TCR therapy: TCR scans of human le white blood cell antigen (HLA) molecules vary widely from patient to patient, so TCR-T cell therapy needs to be personalized for different patients.
to overcome this barrier, a team led by Andrew Sewell, professor of immunology at Enara Bio and Cardiff University, is developing a TCR-T cell therapy that does not scan HLA but identifies MHC class1-related proteins (MR1).
MR1 protein is the same in different patients and is found in a variety of cancer cells.
this cancer immunotherapy can be widely used without personalization.
the team aims to conduct human trials of the therapy by the end of the year.
TCR-T cell therapy be universal? While the concept of "universal cancer therapy" is attractive, Pinkernell of Medigene says expectations for such treatments need to be cautious.
said: "The best application of this cancer treatment 'window' is not easy to find."
, of Gedeta, points to the complexity of cancer development.
" he said, "The key challenge is to understand how tumors evade immunotherapy and how to find combination therapies for different types of tumors to overcome this problem."
Sewell, of Cardiff University, is slightly more optimistic: "I think it's a bit too much to say about potential 'universal cancer therapies', but we can certainly build T-cells that identify most cancers in all individuals."
I think immunotherapy has the hope of successfully treating most cancers over the next 25 years.
potential for "TCR-T cell therapy" is unclear, in part because it is still in its early stages of development.
leading TCR-T cell therapy program has not yet exceeded Phase II trials.
, however, the scale of T-knife's recent round of A financing suggests that investors are interested in the future of the technology, so TCR-T cell start-ups are worth watching in the coming years.
expert review of Guangdong Xiang Xue Precision Medical Technology Co., Ltd. President, CSO Li Wei antigen-specific T-cell step-by-step immunotherapy has developed into two main directions, one is TCR-T, that is, T-cell receptor engineered T cell therapy;
CAR-T is genetically constructed to express scFv (single-stranded antibody variable region) fusion proteins and connect T-cell signal domains, such as the CROSS-membrane domain CD3-derived ITAM signal domain and the costulation signal domain (e.g. CD28, OX40 or 4-1BB, etc.), and its antibodies target tumor cytoblast antigens (7%-10% of all antigens).
Dembic et al. suggested in the late 1980s that alpha and beta gene transfeding could redirect MHC-1-delivered ion antigens in T-cell-specific identification mouse models.
Tumor intracellular, cytoblast, and extracellular antigens can all be presented by MHC (known in humans as HLA) to form major tissue complexes (pMHCs) and are identified by TCR, so TCR-T can target all protein antigens in cells, including tumor antigens.
the concept of TCR-T was put forward earlier, the TCR technology is more complex, which affects its development progress.
is currently on the market for CAR-T products, TCR-T is still not available.
TCR-T, in addition to identifying more targets, is more effective at treating solid tumors, one reason may be better immersion of solid tumors.
T-cells based on natural signaling paths and is more in line with evolutionary logic.
TCR after nearly 20 years of development, now more and more attention and financial support.
and abroad, in addition to the company that has been developing for many years, including Adaptimmune and GSK, Immatics, Medigene and In addition to Bluebird, Guangdong Xiang Xue Precision Medical Technology Co., Ltd., Shenzhen Innoimmune Co., Ltd., Fosun Kate, Guangzhou Laing Biopharmaceutical Layout TCR-T products, many new TCR-T companies and new TCR-based therapies are also in everyone's sights: like T-knife, TCR for "hunting" cancer was obtained from mice; Zelluna Immunotherapy, focused on TCR-NK cell therapy; and Medigene initiated TCR-T cell therapy, which identifies MHC class 1-related proteins (MR1).
for the development of TCR-T, can be summed up as three generations.
The first generation isolates antigen-specific T-cells from patients, such as tumor-infested T-cells (TL), which, after thymus screening, maintain their wild type TCR in low affinity in order to protect their own T-cells, thus giving tumors a better chance of escaping immunosuppression; After T cell cloning, isolation of wild TCR and transduce of T cells, TCR-T, characterized by the need to separate antigen-specific T cells from patients, but still did not solve the problem of tumor escape immune monitoring;
Xiang Xue Group's Guangdong Xiang Xue Precision Medical Technology Co., Ltd. laid out the third generation of TCR-T products developed TEST16001, and in March 2019 was approved by China CDE for the first TCR-T cell therapy IND.
clinical trials are well under way.
's current global leader in TCR-T is NASDAQ-listed Adaptimmune, which has three targets, MAGE-A4, AFP and MAGE-A10, which is in Clinical Phase II or Phase I, with more focus on the U.S. and European markets.
large number of people in China and even Asia, cancer patients have a large base, and its HLA-type distribution is different from that of people in Europe and the United States, and TCR-T research and development in China has its unique advantages.
current global TCR-T clinical trials (including non-registered clinical studies), the United States and China are in the first gradient, while TCR-T clinical trials in China are increasing year by year.
the current TCR-T treatment of solid tumors, including non-treatable glioblastoma and late metastasis melanoma, has achieved an effective rate of 50%-60%, a considerable number of patients have been fully alleviated.
the distribution and number of TCR-T clinical trials in each country (data from clinicaltrials.gov; picture source: Annals of Blood) However, TCR-T cell immunotherapy needs to be addressed urgently if it is to make more breakthroughs, and there are three major issues that need to be addressed: 1) target screening.
while TCR-T can target all tumor antigens, there are still limited targets that have been proven to be safe and effective, with more than 30 percent of TCR-T clinical trials targeting NY-ES.