US20210308267A1 - Rejuvenation of car t cell - Google Patents

Rejuvenation of car t cell Download PDF

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US20210308267A1
US20210308267A1 US17/266,509 US201917266509A US2021308267A1 US 20210308267 A1 US20210308267 A1 US 20210308267A1 US 201917266509 A US201917266509 A US 201917266509A US 2021308267 A1 US2021308267 A1 US 2021308267A1
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component
car
payload
targeting ligand
drug
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Philip Stewart Low et al.
Boning Zhang
John V. Napoleon
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Purdue Research Foundation
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Assigned to PURDUE RESEARCH FOUNDATION reassignment PURDUE RESEARCH FOUNDATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: NAPOLEON, John V, ZHANG, Boning, LOW, PHILIP STEWART
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Definitions

  • This disclosure provides a system to rejuvenate cancer antigen exhausted chimeric antigen receptor T (CAR T) cells.
  • the system comprising a fusion receptor in a classical CAR construct, wherein the fusion receptor provides a ligand binding module that recognizes a high affinity ligand-payload drug conjugate to deliver payload of drugs that are designed to either block the inhibitory signaling in the exhausted CAR T, or to re-activate CAR T through an antigen independent pathway.
  • CAR chimeric antigen receptor
  • CAR T cells as same as tumor infiltrated lymphocytes (TIL), can be re-educated by this suppressive microenviroment and turn to a “hypofunctional” status, which is characterized by overexpression of co-inhibitory molecules (i.e., PD-1, Tim-3, LAG-3 etc.), decreased INF ⁇ secretion and killing capability.
  • co-inhibitory molecules i.e., PD-1, Tim-3, LAG-3 etc.
  • INF ⁇ secretion and killing capability i.e., PD-1, Tim-3, LAG-3 etc.
  • Data from the patient samples of ovarian cancer shows that the majority of PD-1 + CD8 + T cell lacked expression of CD127, which is known to be important for the effector-to-memory transition in T cell.
  • Overexpression of LAG-3 also negatively correlated with the effector function of TCR specific CD8 + TIL.
  • PD-1 + LAG-3 + double positive T cell exhibited lower INF ⁇ production 2 .
  • NY-ESO-1 TCR specific human T cell became hypofunctional in mice solid tumor model, showing high expression of the co-inhibitory molecules and less efficient anti-tumor effect, due to both the microenvrioment and the constant activation of T cell by the continuous exposure to antigen 3 . Therefore, a reversion of the suppressive microenviroment, more importantly, a rejuvenation of the exhausted CAR T cell is highly desired for a better solid tumor treatment.
  • This disclosure provides system to rejuvenate an exhausted classical CAR T cell.
  • the system comprises at least two components: a first component is a conjugate comprising a targeting ligand covalently linked to a payload of drug; and a second component is a targeting ligand binding module linked to membrane-anchoring module.
  • the targeting ligand binding module of the second component recognizes the targeting ligand in the first component with high affinity to form a complex, and the payload drug either blocks the inhibitory signaling of the exhausted CAR T, or re-activates said CAR T through an antigen independent pathway.
  • the membrane-anchoring module mediates internalization of the two component complex into the exhausted CAR T cell.
  • the aforementioned targeting ligand of the first component is folate, FITC or FK506.
  • the aforementioned targeting ligand binding module of the second component comprises a folate receptor, an anti-FITC antibody fragment or FKBP.
  • the aforementioned membrane-anchoring module is a folate receptor.
  • the aforementioned first component comprises a releasable linker between the targeting ligand and the payload drug.
  • the aforementioned first component comprises a non-releasable linker between the targeting ligand and the payload drug.
  • the binding affinity between aforementioned targeting ligand and the targeting ligand-binding module is in sub-nanomolar range.
  • the aforementioned payload of drug is a Toll Like Receptor 7 (TLR7) agonist or Simulator of interferon genes (STING) agonist.
  • TLR7 Toll Like Receptor 7
  • STING Simulator of interferon genes
  • the aforementioned payload of drug is an inhibitor to following proteins: SHP1/2, TC-PTP or DGK ⁇ , TGF ⁇ .
  • the aforementioned TLR7 agonist has the structure of or
  • the aforementioned first component is a Fluorescein-TLR7 agonist having the structure of
  • the aforementioned first component is a FK506-TLR7 agonist having the structure of
  • the aforementioned first component is one of the following:
  • the aforementioned first component comprising the payload drug selected from the group consisting of following TC-PTP phosphatase inhibitors:
  • the aforementioned phosphatase inhibitor is connected to the fluorescein or FK506 (tacrolimus) to form the following structures:
  • the aforementioned payload drug in the first component comprises a STING agonist of one of the following structures.
  • the aforementioned first component comprises a spacer between the targeting ligand and the payload drug selected from the group consisting of the following structures:
  • This disclosure further provides a method to rejuvenate an exhausted CAR T cell.
  • the method comprises the steps of:
  • the aforementioned method carries a payload drug executing its function within the endosome of the exhausted CAR T, and the targeting ligand and the payload drug are linked by a nonreleasable linker.
  • the aforementioned method carries a payload drug executing its function as a free drug in the cytosol of the exhausted CAR T, and the targeting ligand and the payload drug are linked by a releasable linker.
  • the targeting ligand of the first component is folate, FITC or FK506 in aforementioned method.
  • the targeting ligand-binding module of the second component in aforementioned method is anti-FITC, folate receptor, or FKBP.
  • the targeting ligand-binding module of the second component in aforementioned method is Folate Receptor alpha (FRa).
  • the payload of drug of the first component in aforementioned method is a Toll Like Receptor 7 (TLR7) agonist or Simulator of interferon genes (STING) agonist.
  • TLR7 Toll Like Receptor 7
  • STING Simulator of interferon genes
  • the payload of drug the first component in aforementioned method is an inhibitor to following proteins: SHP1/2, TC-PTP or DGK ⁇ , TGF ⁇ .
  • the TLR7 agonist in aforementioned method has the structure of
  • the first component in aforementioned method is a Fluorescein-TLR7 agonist having the structure of
  • the first component in aforementioned method is a FK506-TLR7 agonist having the structure of
  • the first component in aforementioned method is
  • the first component in aforementioned method comprising payload drug selected from the group consisting of following TC-PTP phosphatase inhibitors:
  • the first component in aforementioned method comprising the Phosphatase inhibitor connected to the fluorescein or FK506 (tacrolimus) to form the following structures:
  • the first component in aforementioned method comprising a payload drug of a STING agonist of the following structures.
  • the first component in aforementioned method comprising a spacer between the targeting ligand and the payload drug that is selected from the group consisting of the following structures:
  • FIG. 1 la, Graph illustration of the exhaustion model. 1b, antiCD19 CAR T cell became exhausted after 3 times of stimulation of fresh Raji cell in vitro as shown by decreased killing effect.
  • FIG. 2 Graph illustration of the secret passageway.
  • FKBP or antiFITC is linked to FRa as a fusion receptor, which constantly internalizes and delivers FK506 or FITC linked payloads into the cell.
  • FIG. 3 Binding affinity of FK506 and FITC to the corresponding fusion receptors.
  • FIG. 4 . 4 a Structure of the TLR7 agonist.
  • 4 b rejuvenation effect of TLR7 agonist on exhausted antiCD19 CART cell, shown as the increased killing effect, INFr level and decreased co-inhibitory molecule level.
  • FIG. 5 Chemical Structure of TLR7 agonists.
  • FIG. 6 in vitro model for the induction of CAR T cell exhaustion.
  • A CD19 + Raji and anti-CD19 CART cells were co-cultured at 1:1 ratio with fresh Raji cells added every 12 h.
  • B Lysis effect of CAR T cells gradually decreased as the number of stimulus (number of Raji cell addition) increases.
  • CD19 ⁇ K562 cells were used as control.
  • C Expression level change of co-inhibitory molecules, PD-1, LAG3 and Tim3 for stim1 and stim3 in CD4 and CD8 positive CAR T cells.
  • FIG. 7 Evaluation of TLR7 agonist and PTP1b inhibitor effect on rejuvenation of exhausted CART cells.
  • FIG. 8 Evaluation of potential derivatization sites of the TLR7 agonist for non-releasable ligand targeted delivery.
  • A Chemical structure of the TLR7 agonist analogs.
  • B Exhausted CART cells were incubated with different concentration of TLR7 analogs and lysis effect was measured and compared to non-treated group.
  • FIG. 9 Design and evaluation of releasable and non-releasable targeted delivery of TLR7 agonist using FITC as a targeting ligand.
  • A Illustration of chemical structure of FITC-TLR7 agonist.
  • FIG. 10 Chemical linkers of variable rigidity and hydrophobicity available for usage in the design of targeting ligand-payload conjugates.
  • Chimeric antigen receptor (CAR) T cell therapies have recently experienced substantial success in the treatment of several types of hematopoietic cancers. In the meantime, one should also recognize that some of the lymphoma and most solid tumor cases still have a very low response rate or a high relapse rate with CAR T cell therapies. This mainly result from one or combinations of the following three reasons: 1. Emergence of antigen negative cancer cell colonies under the selection pressure of CAR T cells, as seen in the case of CD19 negative ALL relapse treated with anti-CD19 CART cells; 2. Hindered initial homing and proliferation of CART cells in solid tumor due to the aberrant tumor vasculature, dense stromal barrier and suppressive microenvironment; 3.
  • This FITC-FR fusion receptor is composed of two parts, scFv against FITC as the ligand binding domain at the N terminal and FRa as the GPI anchoring and internalizing domain at the C terminal.
  • the FITC-FR fusion receptor can be specifically targeted by a FITC-immuno agonist to overcome the exhaustion status of CAR T cells in the suppressive tumor microenvironment.
  • These immuno-agonists normally cause strong autoimmunity side effects, and can now be systemically dosed in a FITC targeted form, and safely delivered to FITC-FR positive CAR T cells.
  • CARs chimeric antigen receptors
  • CAR T also known as chimeric T cell receptors, chimeric immunoreceptors or artificial T cell receptors, enable immune effector cells (usually T cells or NK cells) to recognize target cells with corresponding antigen and exercise their cytotoxic activity.
  • immune effector cells usually T cells or NK cells
  • T cells or NK cells immune effector cells
  • Some traditional and improved CAR T cell design are disclosed in U.S. application Ser. No. 15/296,666, the content of which is incorporated herein entirely.
  • a CAR system is produced by providing a cytotoxic lymphocytes expressing CARs that target a moiety that is not produced or expressed by cells of the subject being treated.
  • This CAR system thus allows for focused targeting of the cytotoxic lymphocytes to target cells, such as cancer cells.
  • the targeted moiety is part of a small conjugate molecule (SCM) that also comprises a ligand of a tumor cell receptor.
  • SCM small conjugate molecule
  • Administration of a SCM along with the CAR-expressing cytotoxic lymphocytes results in the tarting of the cytotoxic lymphocyte response to only those cells expressing the tumor receptor to which the SCM is bound.
  • CAR T cell therapy Despite the rapid progress of CAR T cell therapy in both research and clinical use field, there are concerns accompanied with CAR T therapy.
  • One lethal side effect is cytokine storm generated from the fast lysis of tumor cells as well as it kills normal cells bearing CAR.
  • targeted delivery of CAR T cell with specific payload of drug to the target tumor cells to control such side effect is developed in PCT/US2018/018557, the content of which is incorporated herein entirely.
  • an engineered protein is coupled with a high affinity targeting ligand, wherein the targeting ligand carries at least one payload of drug to be internalized by the CAR T cell through the engineered protein to regulate transplanted cell therapy effects.
  • CAR T therapy Another limitation of CAR T therapy is their tendency to get exhausted after repeated stimulation of cancer antigen.
  • the reversibility of the exhausted phenotype of T cell is proven as T cells isolated from the solid tumor tissue show higher INF ⁇ secretion and killing effect if kept away from antigens (“rested”) overnight before re-stimulation 4 .
  • rejuvenation can be achieved in a more clinical relevant way using drugs: either to block the inhibitory signaling or to activate the T cell through other pathways.
  • Antibodies targeting checkpoint inhibitors i.e. PD-1, CTLA-4, etc.
  • PD-1, CTLA-4, etc. have shown some success in solid tumors in clinic, however, two or more targets in combination are often found to be necessary 5 6 .
  • antibody therapy also suffers from poor penetration in solid tumor.
  • DGK ⁇ is another physiological inhibitor of TCR signaling and it's overexpressed in exhausted TIL. DGK ⁇ catabolize DAG to PA thereby reducing DAG levels, which results in attenuation of Ras and MARK ERK signaling.
  • Inhibitor of DGK ⁇ recovers the degranulation and increases the killing effect of TIL and CAR T 3 9 .
  • Another approach to rejuvenate the T cell is to activate it through an antigen independent pathway. It has been known that certain pathogen pattern recognition (PPR) receptors, including Toll like receptors (TLR), do express on non-myeloid cell populations, including T cells, and can be activated in a similar way. Research has also shown that TLR2 10 , 4 11 and 7/8 12 13 agonists can activate CD8 T cells and increase INF ⁇ secretion.
  • PPR pathogen pattern recognition
  • TLR2 10 , 4 11 and 7/8 12 13 agonists can activate CD8 T cells and increase INF ⁇ secretion.
  • Stimulator of interferon genes is a cytosolic DNA sensor (CDS) that widely expressed in hematopoietic cells in peripheral lymphoid tissues, including T cell, myeloid cells and monocytes. STING agonists have been used as an immune stimulator for many immunotherapies, and may also have a profound effect in CAR T therapy.
  • the system consists a fusion receptor and a classical CAR construct, linked through a T2A self-cleavable sequence.
  • the fusion receptor contains two parts: (1) a ligand binding module, which can recognize a high affinity ligand-payload conjugate; (2) a membrane bound receptor module, which can mediate the internalization of the receptor/conjugate complex into the cell.
  • FKBP/FK506 and scFv against FITC (4M5.3)/FITC Two protein/ligand pairs have been chosen for part 1, FKBP/FK506 and scFv against FITC (4M5.3)/FITC, for the following reasons: (1) the absence of FKBP or 4M5.3 on natural cell membrane guarantees the specific delivery of payload to fusion receptor positive CAR T cell, thus reduces the side effects to other cells; (2) the sub-nanomolar binding affinity between protein/ligand pairs promote sufficient payload accumulation inside the targeted cells.
  • Folate Receptor alpha (FRa) was chosen for its constitutive internalization properties regardless of Folate Acid binding 16 .
  • TLR7 locates in the endosome, secret passageway delivered TLR7 agonist can exert its function as soon as it enters the endosome through receptor mediated internalization. Therefore, releasable linker is not necessary in this case. While for other targets that are located in the cytosol instead of the endosome, such as SHP1/2, TC-PTP, DGK, TGF ⁇ and STING, release of the free drug from the target-payload conjugate is necessary for its escape from the endosome. Together, this secret passageway system provides a versatile platform for specific in vivo delivery of numerous payloads to the exhausted CAR T cell.
  • AntiCD19 CAR T cell were co-cultured with Raji at 1:1 ratio in 6 well plate, while fresh Raji cell were added every 12 h to the same well. Killing effect and co-inhibitory markers were quantified by flow cytometry counting. For drug treatment, after 4 rounds of stimulation with Raji cells, exhausted antiCD19 CAR T were further incubated with drugs at different concentration for 12 h, and then quantified similarly
  • Fusion receptor positive cells were incubated with certain ligand-dye molecule at different concentrations for 30 min at 4 degree. After incubation, cells were washed twice with PBS and then submitted to flow cytometry. MFI or percentage of shift is used for binding curve and calculation of Kd.
  • DMEM fetal bovine serum
  • penicillin-streptomycin was used for the culture of MDAMB-231 and MDA-MB-231 CD19 + cells.
  • Peripheral blood mononuclear cells PBMCs
  • PBMCs Peripheral blood mononuclear cells
  • Pure CD3+ T cells were enriched from PBMCs using an EasySepTM Human T Cell Isolation Kit (STEM CELL technologies, #17951).
  • anti-CD19 CAR T cells were co-incubated with CD19 + Raji cell at 1:1 ratio in 12-well plate at density of 2 ⁇ 10 6 CAR T and 2 ⁇ 10 6 Raji per well, new Raji cell were added every 12 h for 3 times, Raji cell population, lysis effect and co-inhibitory receptors were then tested to confirm the exhaustion of the CART cells. Both flow cytometry and luciferase-based assays were used to quantify the lysis effect. To test the rejuvenating efficacy of the potential payloads, this cell mixture was then transferred to 96-well plate, around 2 ⁇ 10 5 cells per well, and different concentration of drugs were added. After 12 h, Raji cell population, lysis effect and co-inhibitory receptors were tested again and compared to the PBS treatment group.
  • FIG. 1 a shows Raji cells, a type of B-lymphoma cells were co-cultured with FMC63 CAR T cells, a type of anti CD19 CAR T cells as described in the method section, and fresh Raji cells were added to the co-culture every 12 hours for consecutive three days.
  • FIG. 1 b shows these CAR T cells became exhausted after 3 times of stimulation by fresh Raji cells in vitro, indicated by decreased killing effect.
  • Co cultured K562 cells served as negative control.
  • FKBP or antiFITC is linked to FRa as a fusion receptor, which is able to engage a targeting ligand FK506 or FITC linked to a specific payload of drug. Due to the nature of FRa, it constantly internalizes and delivers FK506 or FITC linked payloads into the CART cell. Therefore, when CAR T is engaged to its target cells through CAR, in this example, anti-CD 19 molecule on the CAR T surface engages CD-19 of the cancer cell, the delivered payload drug inside of CAR T may execute its function, i.e. regulate CAR T activity based on the payload function. For example, some payload drugs may be directed to act on PD-1, CTLA4, or LAGS T cell function regulatory molecules to rejuvenate CAR T when necessary.
  • the payload drug is an imaging agent Rhodamine to show the payload distribution in fusion receptor transfected Jurkat cells.
  • FK506-TLR7 agonist conjugate should have one of the structures given below:
  • Fluorescein-TLR7 agonist conjugate should have one of the structures given below and rejuvenate exhausted CAR T if the functional CAR T has an anti-FITC fusion receptor.
  • TC-PTP phosphatase inhibitor should have the following structures,
  • the STING agonist should have the following structure,
  • CAR T cell therapies in solid tumors are their tendency to become exhausted after repeated stimulation with cancer antigens. This phenomenon however, is not specific to CAR T cells, but has been described in both chronic virus infections 4 and tumor infiltration lymphocytes 5 .
  • the reversibility of the exhausted phenotype of T cells has been proven in studies where T cells isolated from the solid tumor tissue show a higher INF ⁇ secretion and a killing effect if kept away from antigens (“rested”) overnight before re-stimulation 57 .
  • rejuvenation could be achieved in a more clinically relevant way using commercially available therapeutics: either to block the inhibitory signaling or to activate the T cells through other pathways.
  • Antibodies targeting checkpoint inhibitors i.e.
  • PD-1, CTLA-4, etc. have shown some success in solid tumors in-clinic 151 , however, two or more targets in combination often have been found to be necessary. Moreover, antibody therapy also suffers from poor penetration in solid tumors and this may have led to less reports for the combination therapy of CAR T cells and checkpoint blockades (ICB) in solid tumors.
  • CAR T cells and checkpoint blockades (ICB) CAR T cells and checkpoint blockades
  • SHP1/2 phosphatase is responsible for mediating the signal from PD-1 and other exhaustion markers.
  • SHP1/2 phosphatase inhibitor or silencing can increase the activity of T cells and CAR T cells 69 .
  • TC-PTP is known to be an important player in T cell activity signaling. Mice harboring a T cell specific TC-PTP deficiency have increased susceptibility to inflammation and autoimmunity due to heightened antigen-driven T cell activation.
  • TC-PTP inactivates Src family kinase downstream of the TCR, thereby contributing to the threshold of TCR activation 11 .
  • knockout experiments and small molecule inhibitors of these phosphatases have shown potent effect on lowering TCR threshold and increasing T cell activity, none of them have been used in CAR T therapy.
  • a representative SHP1/2 inhibitor has the structure of
  • TLR pathogen pattern recognition receptors
  • PPR pathogen pattern recognition
  • TLR7/8 agonists and TCR signaling can activate CD8 T cells and increase INF ⁇ secretion 13 .
  • TLR agonists due to the strong side effects of systemic dosing of TLR agonists, none of these agonists have been used in CAR T therapy to reactivate the T cell or change the immunosuppressive microenvironment.
  • TLR7 agonist was found in the literature ( FIG. 7A ), which is around 40 fold stronger than the FDA approved imiquimod.
  • TLR7 agonist and PTP1b (highly homologous to TC-PTP 26 ) inhibitor 27 of choice with the already exhausted CAR T cells was shown to be able to reactivate them compared to the no treatment group ( FIG. 7 ). No significant changes, however, were observed in the expression level of co-inhibitory markers except for Tim3. As shown by FIG. 7C , the PTP1b inhibitor in general does not show as strong of a reactivation effect as the TLR7 agonist.
  • TLR7 is one of the 4 TLR family members that resides inside the endo some, it is speculated that a non-releasable linker between the TLR7 agonist and our secret passageway targeting ligand would preserve its TLR7 agonist function 28 .
  • TLR7 agonist analogs were prepared and tested to find the proper derivatization sites for linkage. As shown in FIG. 8 , the TLR7 agonist with a CH 2 OH extension at the piperidine ring has an even higher activity compared to the parent drug. Therefore, this derivative site will be used for a non-releasable conjugate.
  • a disulfide bond linked self-immolative form also has been synthesized.
  • the intra-endosome TLR7 can get to its functional concentration much faster and quicker, resulting in a smaller IC 50 .
  • TLR7 agonist there are several other potential payloads that may revert/prevent the exhaustion of CAR T cells as described below.
  • Some of the targets may not have agonists or inhibitors with IC 50 suitable for our targeted drug delivery approach for now, but are still worth noticing and may be explored through other inhibitory mechanisms, such as CRISPR or targeted microRNA delivery approaches.
  • STING The Simulator of IFN Genes
  • STING is a master adaptor involved in cytosolic DNA sensing and the following IFN- ⁇ production.
  • STING associates weakly to sdDNA, but strongly binds the endogenous cyclic dinucleotide GMP-AMP (cGAMP) synthesized by the cGMP-AMP synthase (sGAS). It is predominantly expressed in macrophages, T cells, a variety of DCs, endothelial cells, and select fibroblasts and epithelial cells.
  • cGAMP endogenous cyclic dinucleotide GMP-AMP
  • sGAS cGMP-AMP synthase
  • STING mainly focused on its function in macrophages and dendritic cells, and recently some groups have noticed the direct effect of STING activation in T cells 40 . It is possible that a STING agonist will have a similar pro-inflammatory effect on T cells.
  • ADU-S100 is one of the
  • DGK-a Diacylglycerol Kinase-a converts diacylglycerol (DAG), a second messenger in TCR signaling together with IP3, to phosphatidic acid (PA).
  • DAG diacylglycerol
  • PA phosphatidic acid
  • DGK is more highly expressed in CD8TIL than in CD8-NIL, and its inhibition promotes ERK phosphorylation and lytic degranulation 41 ; it also restores lytic functions of CAR TIL that are isolated from in vivo 5 .
  • Some DGK inhibitor structures are as following;
  • TGF ⁇ is known for its immunosuppressive function in many immune cells, such as the T cell, B cell, and macrophages.
  • TGF ⁇ RI TGF ⁇ type I receptor
  • ALK5 TGF ⁇ type I receptor
  • Small molecule inhibitors have been pursued with galunisertib (LY2157299 monohydrate) and EW-7197 tested in clinics 43-44 .
  • a TGF ⁇ inhibitor structure is as following:
  • Enhancer of Zeste Homolog 2 is a histone H3K27 methyltransferase with a strong correv with the Treg function. Genetic or pharmacological disruption of EZH2 drove acquisition of proinflammatory function of tumor infiltrating Treg 45 . Since exhausted CTL in chronic virus infections is also characterized by unique epigenetic changes 174 , it is possible that EZH2 inhibitors will be able to reverse this exhaustion status.
  • EZH2 inhibitors Several small molecules of EZH2 inhibitors have been developed, including CPI1205, EPZ6438 and GSK126.
  • the FITC-FR fusion receptor and the corresponding FITC targeted immune-agonists payloads provide a universal platform for the monitor and control of CAR T cells homing and persistence in solid tumor.
  • This approach can be easily incorporated into CAR T cells for any antigen since the FITC-FR fusion receptor is independently expressed to the CAR construct.
  • the modular design of targeting ligand-payload conjugates also makes it easier for the switching and modification. This approach combines the benefits of cell therapy and small molecule-based targeted drug delivery and may require extra characterization of both the engineered cells and the corresponding ligands.
  • CAR T cells in solid tumor most likely requires the combination of multiple approaches targeting other players within the microenvironment as well, such as breaking down of the extracellular matrix by PI3K kinase inhibitors, reprograming of anti-inflammatory M2 macrophages to a proinflammatory M1 phenotype, and upregulation of the decreased MHC molecules level on cancer cells. Therefore, more and more combinational therapy studies will be conducted both preclinically and clinically. However, at the same time, a careful examination and control of the CAR T cell itself cannot be neglected and should be optimized by using simple but robust systems like FITC-FR fusion receptors in preclinical research first before it reaches to humans.

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