CAR-T bitter journey

▲TG-Bio has joined hands with more than 600 industry colleagues and will be opened in April ▲CAR-T cell therapy is currently one of the hottest research directions in the field of tumor cell immunotherapy.
The effect of CAR-T on hematoma makes people see it There is hope for application in solid tumors, but the reality is that CAR-T therapy rarely breaks through in the field of solid tumors.
So far, the development of CAR-T therapy for solid tumors is still in the early stage.
The unfavourable voice in the treatment of solid tumors has not faded, especially after Novartis, the big brother in the CAR-T field, announced that it would abandon the internal development of CAR-T treatment of solid tumors, and various voices of bad news have been heard everywhere.

So, is solid tumor really an insurmountable mountain for CAR-T? Should solid tumors be overcome? There are many obstacles to find the target → CAR-T cell catching blind CAR-T therapy can treat hematological tumors.
The first thing to rely on is the specific recognition of hematological tumor antigens, so as to achieve specific killing of tumors.

A basic prerequisite for this effect is that the target antigen is specifically expressed on the tumor.

This is not the case in solid tumors.
It is difficult to find specific target antigens in solid tumors.
The solid tumor antigens that can be found at present are not perfect.
They are expressed more or less on normal cells (even if they are very small), so use It is difficult to avoid its attack on normal cells during this therapy.

Note: Common solid tumor targets such as HER2, CEA, EGFR, GD2, PSMA, Mesothelin, MUC1, etc.
are all tumor-related targets, which are highly expressed in tumors, but also have a small amount of expression in normal tissues.

In addition, tumor cells can also avoid the attack of CAR-T cells by reducing or changing the expression of surface antigens, which further increases the risk of off-target at this level.

Unable to penetrate into tumor tissues---the lack of motivation to solve the problem of finding specific target antigens for solid tumors is just the first step in the long march of CAR-T treatment of solid tumors.
Even after CAR-T cells can detect solid tumors, they can penetrate Going inside the tumor tissue still faces a series of obstacles.

First of all, CAR-T cells are restricted to blood vessels.
There are multiple mechanisms in tumor tissues that down-regulate the expression of molecules that mediate immune cell exudation in blood vessels, and ultimately inhibit T cells from penetrating the blood vessel wall and entering the tumor tissue.

In addition, after CAR-T cells come out of blood vessels, they need to pass through a physical barrier formed by dense tumor tissue.
This barrier makes the migration process of CAR-T cells to target cells difficult.

At the same time, solid tumors lack chemokines (expressed at low levels in solid tumors) that can drive CAR-T cells to migrate to target cells.
Therefore, CAR-T cells are insufficiently motivated.
The above obstacles make even CAR-T cells in After finding the target, it is also difficult to penetrate into the tumor tissue.

Severe tumor microenvironment → battle of survival and death The harsh tumor microenvironment that CAR-T will face after reaching the tumor site can not be described as embarrassing on all sides.

Environmental conditions such as hypoxia, low pH, and lack of nutrients in tumors are not conducive to the proliferation and activation of T cells.

In addition, there are many immunosuppressive cells in the tumor microenvironment, such as regulatory T cells (Treg), myeloid-derived suppressor cells (MDSC), M2 tumor-associated macrophages, etc.
These immune cells and the cytokines secreted by them, Such as transforming growth factor-β (TGF-β) and interleukin (IL)-10, etc.
, which severely inhibit the anti-tumor effect of CAR-T cells in solid tumors, so this has also become an inhibitor of CAR-T's therapeutic effect A big shackle.

In addition to overcoming the above-mentioned major hurdles, the most difficult one is to control the intensity of CAR-T therapy in solid tumors.
It cannot be too high to cause serious side effects, nor too low to make the treatment ineffective.
The optional range of CAR-T treatment intensity in solid tumors is much smaller than that of hematological tumors. All the above is the real dilemma faced by CAR-T cells in the treatment of solid tumors, so will CAR-T give up lightly? Of course not, many CAR-T R&D companies will still not hesitate to incorporate solid tumor R&D into their corporate plans.

It is reported that the total number of hematological tumor patients accounts for only 10% of all tumor patients, while the total number of solid tumor patients accounts for as much as 90%.

At present, CAR-T therapy is mainly used for the end-line treatment of hematoma.
Take the end-line patients of lymphoma, the domestic population of this group is only about 10,000.
With such a small number of patients, double-digit R&D companies have Let this market be equivalent to a "red sea"", Fosun Kate CEO Dr.
Liqun Wang once said in an interview.

Therefore, under the increasingly homogeneous situation of CAR-T R&D, it is difficult for companies to recover R&D costs solely by developing hematomas.
.

Therefore, enterprises layout of solid tumors is not so much due to the huge market potential in this field field induces, as it is subject to increasingly fierce market competition drives, to make CAR⁃T cell therapy can also be used in the treatment of solid tumors, either Both academia and clinical circles are trying to make breakthroughs.

Optimize CAR-T cells (improve the adaptability in solid tumors).
Use different strategies to optimize CAR-T cells to make them more suitable for solid tumors.
For
example, make CAR -T cells more suitable for solid tumors.
-T cells express IL-12 to improve their survival ability and anti-tumor activity in vivo, or by expressing CXCR2 to improve the ability of T cells to migrate into tumor tissues.

In addition, PD1-CD28 chimera can also be constructed Receptor, which reverses the immunosuppressive signal into an activation signal, so as to achieve the purpose of resisting the PD-L1/PD-1 immunosuppressive microenvironment.

There are many attempts and researches on such micro-innovations to optimize CAR-T cells.
I repeat them one by one.

Multi-target coverage (to broaden the coverage of tumor cells) Current CAR-T in solid tumor clinical research is mostly single-targeting, solid tumors themselves have antigenic heterogeneity, so single-target CAR -T makes a lot of fish that slip through the net, and its kill coverage is relatively limited.

Therefore, it is envisaged to broaden the coverage of tumor cell killing through multi-target CAR-T cell combination, which is also expected to further improve the survival benefit of patients.

At present, this multi-target (dual-target or even multi-target) CAR-T therapy strategy has been applied in the treatment of B-cell leukemia.

Genetic engineering (reducing off-target risk) reduces the off-target risk by improving the tumor-specific recognition ability of CAR-T cells.

For example, use genetic engineering to construct inhibitory CARs to prevent CAR-T cells from attacking normal tissue cells, or construct dual-targeted CAR-Ts to ensure that CAR molecules can only recognize two antigens at the same time.
Play the activation function.

Combination therapy eliminates obstacles (resistance to immune suppression) In addition to optimizing and transforming CAR-T cells themselves, combination therapy is also an effective strategy to improve the therapeutic effect of CAR-T cells in solid tumors, such as combining CTLA-4 and PD -1 and other immune checkpoint inhibitors, chemotherapy and radiotherapy, etc.
, to clear obstacles for CAR-T cells, reverse T cell depletion, and give full play to its anti-tumor activity.

This combination therapy has been applied in the treatment of hematological tumors.

 The editor concludes that the current application of CAR-T technology on solid tumors is still based on trials.
Although the results are not obvious, no matter whether it is basic research or clinical research, there is no evidence that this road is completely unworkable and solid tumors are still There is a lot of room for development.

In general, solid tumors and hematological tumors do have completely different characteristics.
The development of CAR-T therapy for solid tumors must not completely copy hematological tumors.
For current Chinese companies, how to take up this challenge and seize the rare opportunity Opportunities for the opportunity, April 9, 2021, the second TG-Bio 2021 immunotherapy technology conference will open in Shanghai, the conference will be from early solid tumor target screening to clinical design, from T cell therapy to NK cell therapy and other dimensions The technological difficulty of impacting solid tumors. This conference invites 40+ senior management personnel from well-known pharmaceutical companies/clinical institutions and 600+ professional audiences to attend the conference.
Multiple focus panels will discuss the most cutting-edge progress in immunotherapy and comprehensively analyze the latest development trends in immune cell therapy! Not to be missed! We are ready, waiting for you to start together! Reference 1.
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