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TCR-T overcomes solid tumors and CAR-T for hematoma
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TCR-T overcomes solid tumors and CAR-T for hematoma. Summary of TCR-T therapy with positive clinical results for solid tumors.
As a potential solid tumor therapy, the number of TCR-T clinical trials has shown an overall upward trend in the past ten years, and the vast majority of indications targeted are solid tumors (about 84%).
In terms of target selection, more than half of clinical trials target CT antigens, of which NY-ESO-1 has become the preferred target antigen, and neoantigens are very few. In fact, there are not many reports of positive clinical data.
Figure 1 The number, indications and antigen types of TCR-T clinical trials carried out from 2004 to 2018
(Source: Technology in Cancer Research & Treatment, compiled by Fengshuo Venture Capital)
1 Summary of TCR-T Therapy with Positive Clinical Results in Treating Solid Tumors
First of all, from the clinical data:
The developed TCR cell therapy Ia dose escalation clinical trials showed anti-cancer activity.
10 patients with evaluable solid tumors (including non-small cell lung cancer (NSCLC), squamous cell cancer), head and neck squamous cell carcinoma (HNSCC), head and neck cancer, melanoma, ovarian cancer and synovium Sarcoma (Synovial Sarcoma) had received at least two pre-treatments and all were ineffective, and 8 patients had received at least one immune checkpoint inhibitor treatment.
The treatment results showed that: 1 case had disease progression (PD), 8 cases had stable disease (SD), and 1 case achieved partial remission (PR).
The tumors of 8 patients shrank, and the tumors of patients with synovial sarcoma shrank nearly 40%.
The phase I clinical trial results of the developed TCR cell therapy ADP-A2M4 targeting MAGE-A4 showed that 16 patients with synovial sarcoma who had previously received chemotherapy received the TCR-T therapy, and the PR reached 50% (not including unconfirmed In one case, the PR was 44%), the median duration of response was 28 weeks, and the progression-free survival period was 20 weeks.
The duration of remission in the two patients who obtained PR has exceeded 72 weeks, and the median overall survival period was not reached.
During the one-year follow-up, 3 of the 7 interviewees continued to benefit. Makes Adaptimmune confident to market ADP-A2M4 in 2022.
Announced Phase I clinical data of TC-210.
The enrolled patients had received at least one treatment for metastatic and/or unresectable tumors in the early stage, and 5 patients (4 mesothelioma (MPM), 1 ovarian cancer) received the first dose group (5*107 cells) /m2) Among the patients treated with TC-210 TRuC-T cells, 2 cases had remission (ORR=40%, 2/5), 2 PRs (1 confirmed, 1 uncertain), disease control rate (DCR) It is 100% (5/5).
Phase III randomized clinical trial of Tebentafusp, a TCR therapy developed for metastatic uveal melanoma.
378 patients were enrolled. Tebentafusp therapy and the researcher’s choice therapy (82% Keytruda, 12% Yervoy, 6% Dacarbazine) were randomly divided into groups at a ratio of 2:1.
The clinical results showed that the HR of the Tebentafusp group was only 0.51 of that of the control group. (95% CI: 0.36, 0.71), p<0.0001, which means that Tebentafusp reduces the risk of progression or death in 49% of patients.
Kaplan-Meier survival analysis showed that the 1-year OS was approximately 73% vs 58%.
This is the first bispecific TCR therapy to obtain survival benefit data in solid tumors. More phase III clinical data will be announced at the academic conference in the first half of 2021.
The Phase I clinical results of the developed KITE-718 TCR-T therapy for solid tumors showed that 17 patients with metastatic solid tumors received the TCR-T therapy after chemotherapy.
Four patients experienced different degrees of remission, of which one patient with metastatic cervical cancer obtained CR for 29 months.
In the other 3 patients, tumor shrinkage was observed, and after one month of treatment, the level of TCR-T cells in the patient’s body increased significantly.
One of the 3 patients with urothelial cancer was still in PR status at the 19th month after treatment.
From a technical point of view:
At present, the usual practice for trials with positive clinical results is to screen out target peptides that exist in tumor tissues rather than normal tissues through their respective technology platforms, and then use genetic engineering methods to obtain a TCR library, from which a pair is screened.
For the TCR with the best affinity and specificity of the target peptide, the last step is to test the cross-reactivity and off-target effects of the TCR.
2 Challenges of TCR-T in the treatment of solid tumors
The most important thing for TCR-T therapy is to select safe and effective antigens as targets.
In addition to the differentiation antigen gp100 or MART-1 for special cancers like melanoma, CT antigen is the most used TCR-T therapy, and it has also been proven to be a safe and effective target in clinical trials.
Immatics, the gold attractor in the TCR-T field, which has traded with many giants (in 2013, it reached a cooperation with Roche for more than 1 billion US dollars; in 2017, it reached a transaction of more than 1.3 billion US dollars with Amgen; in 2018, with the Danish Genmab company Reached a drug discovery and development agreement of US$550 million; reached a US$1.5 billion deal with Celgene in August 2019; reached a US$1.15 billion deal with GSK in 2020) is the best example, Immatics’ R&D pipeline layout The corresponding targets are all CT antigens, and the data from phase I clinical trials show that all adverse events are short-lived and easy to control.
However, the choice of CT antigen does not mean peace of mind, and there may also be a hidden crisis. A more profound understanding of this point is the target of the research and development pipeline, and all of them are Adaptimmune for CT antigens.
When we look at Adaptimmune now, it looks like a bright spot. When we look at its stock price, we will find that there was a surge (216% and 128%) in January and May 2020, and the triggering events were the release of positive clinical data for solid tumors.
But looking back at history, we will find that CT antigen is not as reliable as we take it for granted!
In 2011, in a clinical trial of TCR targeting MAGE-A3 developed by Adaptimmune for the treatment of solid tumors by the team of Professor Carl June of Penn University, the first two patients receiving TCR-T therapy quickly developed cardiogenic shock and died within a week The follow-up investigation found that the reason was that the TCR targeting MAGE-A3 could bind to the myonectin in the heart, and the polypeptide presented by the MHC was very similar to MAGE-A3.
This is why when screening TCR today, even if the target is CT antigen, it is necessary to use high-throughput, ultra-sensitive mass spectrometry and other means to determine that the TCR only exists in tumor tissues and not in healthy tissues.
Follow-up verification whether there is Cross-reaction is an essential link. Of course, these steps can be omitted for some well-known antigens such as NY-ESO-1.
As for the more fashionable new antigen targets, for TCR-T treatment of solid tumors, the steps are too big, let the bullet fly for a while.
Neoantigens are generated by genetic mutations, and there are large differences between individuals, which means that energy production is not possible, and the personalized TCR cloning process usually takes 6-8 weeks to complete under the existing manufacturing process. The virus is constructed under good GMP.
It also takes 6 months and approximately US$250,000 to carry the vector and to test its safety.
During this period, the patient’s tumor will continue to deteriorate; secondly, due to the heterogeneity of the tumor, the same gene mutation will not occur.
In all tumor cells, this means screening TCRs for multiple neoantigens; and there is currently no good algorithm for neoantigen prediction.
Therefore, in the short term, the possibility of commercialization of personalized solid tumor TCR-T therapy is very low.
Solid tumors have the characteristics of complex immunosuppressive microenvironment and inherent heterogeneity, which will limit the clinical effects of TCR-T by reducing the expression of HLA.
A possible solution is to modify the TCR. For example, Immunocore uses an anti-CD3 single-chain antibody fragment (scFv) with enhanced affinity attached to the TCR. This antibody can recruit and activate T cells and is not selective, avoiding T cell depletion. Enhance the immune response.
Other methods are combined with immune checkpoint inhibitors, but immune checkpoint inhibitors such as PD-1 blockers work best in tumors with high genetic mutation burden, such as colorectal cancer, breast cancer, and pancreas. Few can play a role in cancer and prostate cancer.
TCR-T is one of the most promising methods for the treatment of solid tumors. It is the best endorsement by various giants to buy and buy one after another.
Target selection, safety evaluation, and immune escape overcoming solid tumors are the keys to the TCR-T field.
It remains to be seen whether the leading companies in these areas can replicate CAR-T’s brilliance in the field of hematoma treatment.
TCR-T overcomes solid tumors and CAR-T for hematoma
(source:internet, reference only)