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In the past five years, the FDA has approved six CAR-T therapies for non-solid tumors: four for relapsed/refractory B-cell malignancies and two for relapsed/refractory multiple myeloma
.
However, the latest global cancer data for 2021 indicates that about 90% of cancers are caused
by solid tumors.
Although CAR-T has made progress in the treatment of hematological cancers, it has not achieved good efficacy
in solid tumors and treatment.
The antigen characteristics of solid tumors and their tumor microenvironment constitute a "moat", which makes it difficult for CAR-T to be "close", and it is also the
crux of the refractory treatment of solid tumors.
After 10 years of tracking, it was confirmed that CAR-T can treat hematological tumors, and the battle for solid tumors was started Carl June is an immunologist at the University of Pennsylvania.
The world's first CAR-T treatment was
designed.
As the world's first laboratory to conduct human research on CAR-T cell technology, Carl June's Cell Immunotherapy Laboratory at the University of Pennsylvania has been focused on improving and developing new T-cell-based therapies and has discovered many key technologies and fundamentals
.
As a weather vane of CAR-T technology, Carl June began to tackle solid tumors after determining that CAR-T can treat hematological tumors
.
Recently, Carl June announced a collaboration with oncolytic virus company Candel Therapeutics to further verify whether Herpes simplex virus (HSV) vectors can help CAR-T penetrate the solid tumor microenvironment and overcome solid tumors
.
at all.
To test this idea, over the past 10 years, Carl June and immunologist Joseph Melenhorst have regularly collected blood from the first patients in the 2011 trial, tracking changes in
CAR-T cells and cancer cells.
On February 2, 2022, the tracking results were published in Nature under the title "Decade-long leukaemia remissions with persistence of CD4+ CAR T cells" (Figure 2).
This result shows that CAR-T cells are still active ten years after treatment, and although they are in low numbers, they are still measurable
.
By culturing the extracted CAR-T and cancer cells in a petri dish, it was found that these CAR-T cells retained the ability to kill cancer cells
.
it.
" Based on these results, we can now conclude that CAR-T cells can actually cure patients with hematological tumors, and solid tumor research can also go further
.
"
CAR-T and hematological tumors: the narrow road meets the "bright" wins
The effectiveness rate of CAR-T in treating refractory hematological tumors that are ineffective with existing therapies is as high as 50%-70%.
So, what is the reason for the failure of CAR-T?
foe.
Therefore, in order to improve the "resolution" of CAR-T cells on cancer cells and make CAR-T "see clearly", multi-target CAR-T research is in full swing
.
The first is the selection and verification of targets, followed by the optimization of multi-target structure, and finally the technical optimization and product development
of the new CAR-T.
In the future, CAR-T cells with shotguns for guns will make a big difference!
"High cold" solid tumors, rejecting CAR-T thousands of miles away The existing CAR-T products are all aimed at non-solid tumors such as hematological tumors, and they are really powerless
in solid tumors 。 On the one hand, solid tumor cells lack the heterogeneity of antigens --- localized characteristics and specific tumor antigens (TSA), which makes it difficult for CAR-T to accurately target and kill tumor cells.
On the other hand, the special tumor microenvironment (TME) of solid tumors, including the first physical barrier composed of abnormal vascular structure and matrix components, and the secondary barrier composed of a variety of immunosuppressive cells, inhibitory immune and metabolic molecules in TME (Figure 4), the "moat" formed by the two barriers, so that CAR-T cells "cannot cross the river" and cause them to "die before they get out of the army" [2]
。 Fig.
4 Classification of tumor microenvironment (Source: [3]).
Candel Therapeutics: HSV vectors remove barriers to CAR-T treatment of solid tumorsCandel Therapeutics, in collaboration with Carl June, is a clinical-stage biopharmaceutical company developing novel viral immunotherapies, Viral immunotherapies focused on helping patients fight cancer by eliciting systemic anti-tumor immune responses (Figure 5).
Candel's engineered virus aims to induce immunogenic cell death through direct virus-mediated cytotoxicity of cancer cells, thereby releasing tumor neoantigens while creating a pro-inflammatory microenvironment
at the injection site.
Figure 5 Candel Therapeutics platform (Source: Candel Therapeutics official website) Candel has established two clinical-stage viral immunotherapy platforms based on novel transgenic adenovirus and herpes simplex virus gene constructs (Figure 6).
CAN-2409 is a prime product candidate for adenovirus platforms targeting brain, prostate, lung, and pancreatic cancers
.
CAN-3110 is a prime product candidate for the HSV platform for brain cancer
.
The enLIGHTEN™ Discovery Platform is the first HSV-based system iterative discovery platform
that leverages human biology and advanced analytical techniques to create new viral immunotherapies for solid tumors.
.
Candel injects its vehicle directly into the tumor or surrounding tissue to avoid systemic side effects
.
CAN-3110 is an HSV-based treatment designed to place key viral replication genes under
the control of tumor-specific promoters.
Despite the presence of an overall inhibitory environment, these modifications enable CAN-3110 to replicate
aggressively and specifically within tumor cells.
In animal models, this effect produces strong oncolytic cell activity (Figure 7).
Figure 7 CAN-3110 design principle (Source: Candel Therapeutics official website) Candel's research shows that HSV is more effective than oncolytic viruses such as adenoviruses, and they can be better retained at the tumor site, thereby improving CAR-T cell activity
.
HSV also has a larger DNA capacity, meaning multiple genes can be inserted into the
same vector.
If it is injected into a specific tumor, the tumor microenvironment can be modulated so that CAR-T cells can enter the tumor
.
Dr.
Paul Peter Tak, President and CEO of Candel, explains the main differences between HSV-CAR-T and other methods: "Other methods either focus on delivering viruses with specific CAR-T cell antigens or combine CAR-T with systemic viruses to broadly activate immune cells or target individual elements
of TME.
Our innovative approach enables the identification and testing of the best gene combinations to arm vectors
in a preclinical setting.
Use a data-driven approach based on human biology to prioritize targets and computer models to select the best combination of payloads to reduce the risk
of studying drugs during iterations.
In addition, speaking about the collaboration with Carl June, Tak said: "Over the past two years, we have quietly completed the preliminary work and achieved satisfactory results
.
The University of Pennsylvania is a world leader in CAR-T cell development, and by partnering with the University of Pennsylvania, we will show the world what we've been doing
.
" Based on the flexibility of the technology, and the severity of the disease planned for treatment, I believe that if it goes well from a scientific perspective, this will be a relatively fast path
forward.
I don't think anyone can move
in this area faster than Candel in terms of overall capacity.
”
Decade-long leukaemia remissions with persistence of CD4+ CAR T cells.
Nature.
2022 Feb; 602(7897):503-509.
doi: 10.
1038/s41586-021-04390-6.
Epub 2022 Feb 2.
PMID: 35110735; PMCID: PMC9166916.
[2] GUO Feifei, CUI Jiuwei.
Existing challenges and optimization strategies of CAR-T cells in the treatment of solid tumors[J].
Chinese Journal of Clinical Oncology,2022,49(12):617-621.
) [3]Binnewies M, Roberts EW, Kersten K, et al.
Understanding the tumor immune microenvironment (TIME) for effective therapy.
Nat Med.
2018 May; 24(5):541-550.
doi: 10.
1038/s41591-018-0014-x.
Epub 2018 Apr 23.
PMID: 29686425; PMCID: PMC5998822.
.
However, the latest global cancer data for 2021 indicates that about 90% of cancers are caused
by solid tumors.
Although CAR-T has made progress in the treatment of hematological cancers, it has not achieved good efficacy
in solid tumors and treatment.
The antigen characteristics of solid tumors and their tumor microenvironment constitute a "moat", which makes it difficult for CAR-T to be "close", and it is also the
crux of the refractory treatment of solid tumors.
After 10 years of tracking, it was confirmed that CAR-T can treat hematological tumors, and the battle for solid tumors was started Carl June is an immunologist at the University of Pennsylvania.
The world's first CAR-T treatment was
designed.
As the world's first laboratory to conduct human research on CAR-T cell technology, Carl June's Cell Immunotherapy Laboratory at the University of Pennsylvania has been focused on improving and developing new T-cell-based therapies and has discovered many key technologies and fundamentals
.
As a weather vane of CAR-T technology, Carl June began to tackle solid tumors after determining that CAR-T can treat hematological tumors
.
Recently, Carl June announced a collaboration with oncolytic virus company Candel Therapeutics to further verify whether Herpes simplex virus (HSV) vectors can help CAR-T penetrate the solid tumor microenvironment and overcome solid tumors
.
Figure 1 Carl June (Source: University of Pennsylvania official website)
at all.
To test this idea, over the past 10 years, Carl June and immunologist Joseph Melenhorst have regularly collected blood from the first patients in the 2011 trial, tracking changes in
CAR-T cells and cancer cells.
On February 2, 2022, the tracking results were published in Nature under the title "Decade-long leukaemia remissions with persistence of CD4+ CAR T cells" (Figure 2).
This result shows that CAR-T cells are still active ten years after treatment, and although they are in low numbers, they are still measurable
.
By culturing the extracted CAR-T and cancer cells in a petri dish, it was found that these CAR-T cells retained the ability to kill cancer cells
.
Figure 2 Research results (Source: [1])
it.
" Based on these results, we can now conclude that CAR-T cells can actually cure patients with hematological tumors, and solid tumor research can also go further
.
"
CAR-T and hematological tumors: the narrow road meets the "bright" wins
CAR-T (Chimeric Antigen Receptor T-Cell) is called chimeric antigen receptor T cell
.
It is an immunotherapy
that kills tumors through the body's own immune cells.
The basic preparation process of CAR-T therapy is: extract T cells from the immune system from the patient's blood, and equip T cells with "navigation devices" ---CAR (tumor chimeric antigen receptors) in a laboratory environment, turning T cells into "hawk-eye warriors" so that they can specifically recognize cancer cells; "Modified" and expanded to a certain number of "eagle eye troops" are infused back into the patient, confronting cancer cells head-on, using the body's own immune response to destroy cancer tissue
.
The immune system can eradicate cancer from the inside by modifying the body's natural defenses, offering unparalleled advantages over standard treatment (Figure 3).
The effectiveness rate of CAR-T in treating refractory hematological tumors that are ineffective with existing therapies is as high as 50%-70%.
So, what is the reason for the failure of CAR-T?
Table 1 CAR-T product information listed worldwide
Data source: FDA, NMPA and official websites of each companyMapping: It is not difficult for the biological exploration editing team to find that the existing CAR-T products have a single target, but the cunning cancer cells are "multi-faceted", and if you want to rely only on a single information to find cancer cells in the vast "sea of blood", it is inevitable that you will miss it; In addition, the "weapon" of CAR-T cells after entering the "battlefield" is lost, or smart cancer cells adjust their strategies to hide their locked features, so that CAR-T cells cannot find their direction; Moreover, the "weapon" of CAR-T cells does not recognize the unique "ID" of the tumor, but the tumor-related features, which are also normal cells, which will cause CAR-T cells to "mistrack" and distinguish between friend andfoe.
Therefore, in order to improve the "resolution" of CAR-T cells on cancer cells and make CAR-T "see clearly", multi-target CAR-T research is in full swing
.
The first is the selection and verification of targets, followed by the optimization of multi-target structure, and finally the technical optimization and product development
of the new CAR-T.
In the future, CAR-T cells with shotguns for guns will make a big difference!
"High cold" solid tumors, rejecting CAR-T thousands of miles away The existing CAR-T products are all aimed at non-solid tumors such as hematological tumors, and they are really powerless
in solid tumors 。 On the one hand, solid tumor cells lack the heterogeneity of antigens --- localized characteristics and specific tumor antigens (TSA), which makes it difficult for CAR-T to accurately target and kill tumor cells.
On the other hand, the special tumor microenvironment (TME) of solid tumors, including the first physical barrier composed of abnormal vascular structure and matrix components, and the secondary barrier composed of a variety of immunosuppressive cells, inhibitory immune and metabolic molecules in TME (Figure 4), the "moat" formed by the two barriers, so that CAR-T cells "cannot cross the river" and cause them to "die before they get out of the army" [2]
。 Fig.
4 Classification of tumor microenvironment (Source: [3]).
To achieve CAR-T treatment of solid tumors, it is necessary to "cross the river" and then fight
accurately.
In essence, "iron needs to be hard", and "Buff" is superimposed on CAR-T through various means to optimize the structure of CAR-T and improve the ability to "distinguish" solid tumors; Secondly, the CAR-T is equipped with a "pioneer" and "crosses the river to build bridges" in front, so that the CAR-T can smoothly enter the solid tumor and conduct joint operations
.
Candel Therapeutics: HSV vectors remove barriers to CAR-T treatment of solid tumorsCandel Therapeutics, in collaboration with Carl June, is a clinical-stage biopharmaceutical company developing novel viral immunotherapies, Viral immunotherapies focused on helping patients fight cancer by eliciting systemic anti-tumor immune responses (Figure 5).
Candel's engineered virus aims to induce immunogenic cell death through direct virus-mediated cytotoxicity of cancer cells, thereby releasing tumor neoantigens while creating a pro-inflammatory microenvironment
at the injection site.
Figure 5 Candel Therapeutics platform (Source: Candel Therapeutics official website) Candel has established two clinical-stage viral immunotherapy platforms based on novel transgenic adenovirus and herpes simplex virus gene constructs (Figure 6).
CAN-2409 is a prime product candidate for adenovirus platforms targeting brain, prostate, lung, and pancreatic cancers
.
CAN-3110 is a prime product candidate for the HSV platform for brain cancer
.
The enLIGHTEN™ Discovery Platform is the first HSV-based system iterative discovery platform
that leverages human biology and advanced analytical techniques to create new viral immunotherapies for solid tumors.
Figure 6 Candel Therapeutics R&D pipeline (Source: Candel Therapeutics official website)
.
Candel injects its vehicle directly into the tumor or surrounding tissue to avoid systemic side effects
.
CAN-3110 is an HSV-based treatment designed to place key viral replication genes under
the control of tumor-specific promoters.
Despite the presence of an overall inhibitory environment, these modifications enable CAN-3110 to replicate
aggressively and specifically within tumor cells.
In animal models, this effect produces strong oncolytic cell activity (Figure 7).
Figure 7 CAN-3110 design principle (Source: Candel Therapeutics official website) Candel's research shows that HSV is more effective than oncolytic viruses such as adenoviruses, and they can be better retained at the tumor site, thereby improving CAR-T cell activity
.
HSV also has a larger DNA capacity, meaning multiple genes can be inserted into the
same vector.
If it is injected into a specific tumor, the tumor microenvironment can be modulated so that CAR-T cells can enter the tumor
.
Dr.
Paul Peter Tak, President and CEO of Candel, explains the main differences between HSV-CAR-T and other methods: "Other methods either focus on delivering viruses with specific CAR-T cell antigens or combine CAR-T with systemic viruses to broadly activate immune cells or target individual elements
of TME.
Our innovative approach enables the identification and testing of the best gene combinations to arm vectors
in a preclinical setting.
Use a data-driven approach based on human biology to prioritize targets and computer models to select the best combination of payloads to reduce the risk
of studying drugs during iterations.
In addition, speaking about the collaboration with Carl June, Tak said: "Over the past two years, we have quietly completed the preliminary work and achieved satisfactory results
.
The University of Pennsylvania is a world leader in CAR-T cell development, and by partnering with the University of Pennsylvania, we will show the world what we've been doing
.
" Based on the flexibility of the technology, and the severity of the disease planned for treatment, I believe that if it goes well from a scientific perspective, this will be a relatively fast path
forward.
I don't think anyone can move
in this area faster than Candel in terms of overall capacity.
”
Written | contested articles
Typesetting| Muzijiu
End
Resources:
[1]Melenhorst JJ, Chen GM, Wang M, et al.Decade-long leukaemia remissions with persistence of CD4+ CAR T cells.
Nature.
2022 Feb; 602(7897):503-509.
doi: 10.
1038/s41586-021-04390-6.
Epub 2022 Feb 2.
PMID: 35110735; PMCID: PMC9166916.
[2] GUO Feifei, CUI Jiuwei.
Existing challenges and optimization strategies of CAR-T cells in the treatment of solid tumors[J].
Chinese Journal of Clinical Oncology,2022,49(12):617-621.
) [3]Binnewies M, Roberts EW, Kersten K, et al.
Understanding the tumor immune microenvironment (TIME) for effective therapy.
Nat Med.
2018 May; 24(5):541-550.
doi: 10.
1038/s41591-018-0014-x.
Epub 2018 Apr 23.
PMID: 29686425; PMCID: PMC5998822.
