At present, many domestic enterprises have carried out differentiation transformation on allogeneic CAR-T to explore new ways out.

The allogeneic CAR-T, expected to be a game changer, seems caught in a dilemma.

From the current data, there is still a certain gap in efficacy and durability between allogeneic CAR T and autologous CAR T. Due to immune rejection, current allogeneic CAR-Ts can only achieve low cost, but not high efficiency.

If we only have the price advantage, allogeneic CAR T's position is very embarrassing. It cannot replace autologous CAR T in efficacy, nor can it compare with dual antibody in price.

To understand, the first consideration of CAR T therapy breakthrough commercial dilemma, expand the accessibility should be how to enhance efficacy, improve clinical value at the same time to reduce the cost and efficiency, rather than reduce the cost but let the efficacy of discount.

Of course, we don't define a technology just because it goes wrong, and many breakthrough treatments don't start out well. Moreover, cell therapy is the way forward, no matter how hard it is.

But for an allogeneic CAR-T to be a game changer, it needs to be more than just its low price.

01

Difficulty of curative effect

While CAR T therapies are highly effective, the multimillion-dollar price tag is daunting for the average person. Allogeneic CAR-T therapy is seen as the key to making it accessible.

This is understandable, given that today's approved CAR-T therapies require "personalization," long preparation times and high treatment costs. Allogeneic CAR-Ts, however, were derived from T cells from a healthy donor. These T cells can generate a large number of allogeneic CAR T cells to provide off-the-shelf cell therapies to patients, which makes them potentially ideal for commercializing cell therapies.

Allogene, which is developing general-purpose CAR T cells, has said that cells from a single healthy donor could be used to treat 100 cancer patients.

Theoretically, allogeneic CAR T can perfectly solve the problem of high price and no stock of autogenous CAR T. Yet the gap between theory and reality is deep. In practice, there are some problems in the efficacy and durability of allogeneic CAR T.

Take Allogene's allogeneic BCMA CAR-T candidate ALLO-715. On January 23, 2023, Phase 1a clinical data on ALLO-715 for the treatment of relapsed/refractory multiple myeloma (MM) was published in Nature Medicine. Specifically, at 10.2 months of follow-up, the objective response rate (ORR) was 55.8%, 34.9% of patients achieved a partial response or better, and the median duration of response was 9.2 months.

What is the performance of autogenous CAR T therapy? Take Bristol-Myers Squibb's BCMA CAR-T therapy Abecma for example, for the same indication of MM, ORR reached 72%, complete response rate (sCR) reached 28%, and median duration of remission was 11 months. Legendary Bio's BCMA CAR-T therapy, Carvykti, had an ORR of 98% and an sCR of 82.5%, and did not achieve a median progression-free survival at 28 months of follow-up.

Although no head-to-head clinical trials have been conducted, the current data suggest that allogeneic CAR T is less effective and durable than autogenous CAR T.

The efficacy of allogeneic CAR-T was not superior even when compared with dual antibody. Johnson & Johnson's BCMA/CD3 double antibody had an ORR of 64% and a CR of 39.4% for r/r MM.

So is the problem with ALLO-715 itself? No, poor efficacy and durability have also been observed in other allogeneic CAR T therapies.

For example, CRISPR's CD19 allogeneic CAR-T therapy, CTX110, had an ORR of 58% and a CR of 38% in clinical trials for second-line B-cell lymphoma. For the same indication, Gilead CD19 CAR-T in clinical trials had an ORR of 83% and a CR of 65%.

These clinical data suggest that more work is needed before allogeneic CAR T is as effective as autogenous CAR T.

02

Temporary immune rejection that is difficult to overcome

At present, the biggest challenge in the development of allogeneic CAR T therapy is how to avoid the "killing" between the transfused CAR T cells and human immune cells.

After allogeneic CAR T cells are introduced into the human body, two things happen.

In one scenario, allogeneic CAR T cells proliferate in the human body and take on the original tissues and cells as invaders. This can lead to graft-versus-host disease (GvHD), which can range from rash and jaundice to life-threatening.

In the other case, the human immune cells treat the allogeneic CAR T cells as invaders and reject them, resulting in host-versus-graft rejection (HvG).

Once HvG is present, the patient's own T-cell-mediated immune response may begin to work, resulting in the elimination of allogeneic CAR T-S before they begin to work, thereby affecting their efficacy and durability.

In the first case, there's a way to do it. The reason for this is that the specific TCR receptor on T cells is able to recognize the host cell antigen, so that foreign T cells can be rejected.

Then, we just need to remove its identification weapon TCR, to evade the GvHD. Currently, researchers have been able to use ZFNs, TALENs, CRISPR/Cas9 gene editing methods to knock out the expression of TCR.

The second case, however, is trickier to resolve. The second condition occurs due to the recognition of HLA by TCR on the host cell, but we cannot directly knock out HLA on the surface of allogeneic CAR T.

Because the HLA-expressing cell is a friend of the NK cell. If all HLA knockouts are removed, the allogeneic CAR T cells will be mistaken for invaders and killed by NK cells.

To put it simply, the problem is how to avoid killing both NK cells and T cells. Although it is possible to reduce the immune rejection of allogeneic CAR T by completely eliminating lymphocytes and building a working cell bank, it is still impossible to completely eliminate the immune rejection. Also, more aggressive lymphocyte clearance with drugs has been found to increase the risk of infection.

Overall, there is still a long way to go to solve the problem of allogeneic CAR T immune rejection.

Which brings up an awkward question. In the past, we talked about the grand future of allogeneic CAR-T therapies on the premise that they could be as safe and effective as autologous CAR-T therapies, while also having the advantage of being cheap and off-the-shelf.

But the benefit of allogeneic CAR-T therapy may be less clear if the cost of the treatment is compromised. After all, the goal of reducing efficacy and cost can be achieved with dual antibodies.

Of course, that doesn't mean there's no use for allogeneic CAR-Ts. After all, it's still young.

03

Direction and path of allogeneic CAR-T

Given the history of drug development, the twists and turns facing allogeneic CAR T therapies are not unusual. As a new technology, moving from the lab to a commercially mature product is bound to go through many ups and downs.

For example, autologous CAR-T therapy, which is becoming more and more mature and even internal, is also faced with problems such as inability to proliferate and the treatment effect is not lasting when it just emerged. But as new technologies continue to emerge, and CAR-T has been iterated into its fourth generation, that problem is no longer a problem.

In the future, as the technology evolves and more innovative approaches emerge, the stranglehold on allogeneic CAR T therapy will surely be broken. In fact, there have been a number of domestic enterprises on the allogeneic CAR-T differentiation transformation, to explore a new way out.

Genxi, for example, developed the TruUCAR technology platform. The platform uses a bi-specific CAR design, one for defense, to protect CAR T cells from immune rejection; Another type of CAR is used for attack, targeting tumor antigens to wipe out tumor cells. With the help of this platform, Genxi has developed the allogeneic CAR-T product GC027, which is currently in the phase 1 clinical stage.

For example, Kochi disrupted the genomic sites that encode TCR and B2M to eliminate the expression of TCE or HLA and prevent T cell rejection. At the same time, in order to avoid the rejection of HLA-lacking allogeneic CAR T cells by host NK cells, Keji Pharmaceutical loaded the allogeneic CAR T cells with NK cell surface protein (NKG2A), which can recognize NK cells, to prevent NK cells from accidentally injuring CAR T cells.

Another example is that cyclopentae selectively knocks out parts of HLA at the same time as knocking out TCRS, rather than knocking out the entire HLA-1 class. The advantage of this method is to preserve part of HLA, achieve a better balance between T cell and NK cell rejection, and reduce the rejection reaction of NK and T cells to the transfused cells as much as possible.

Although the clinical effects are not yet known, they are all attempts at innovation. In addition to the above enterprises, there are a number of domestic pharmaceutical enterprises such as Bosheng Ji, North Hundsun, Legendary Biology, etc., for allogeneic CAR-T layout.

In uncharted territory, choice is a gamble, and medicine is even more so. Fortunately, the bet was right and it was humanity that benefited.