The world of advanced therapeutics medicinal products (ATMPs) particularly the cell and gene therapies (C&GT) space has been experiencing outstanding growth over the last few years, with a number of therapies transitioning from clinical research into regular clinical practices. In recent years, new cell types and technologies have been used to overcome challenges posed by current treatments and the nature of the targeted diseases, thus enabling us to treat and, in some cases potentially cure severe disorders. The scientific and R&D efforts led to discovering new ways to engineer cells, enabling some of the most outstanding hurdles in complex disease areas such as oncology, cardiovascular, neurologic, and metabolic disorders to be addressed. In recent years, new cell types and technologies, including CAR-T (Chimeric Antigen Receptor T-cell) therapies, have emerged as a transformative solution to overcome challenges posed by current treatments and the nature of targeted diseases.

Progress in CAR-T Cell Therapy: Key Players and Development Updates

As no CAR-T cell therapy has reached clinical trial phases III/IV, the leading and emerging companies are striving to develop and commercialize novel anti-tumor treatments.

1. Takeda Pharma: Market giant Takeda, having multiple collaborations with Noile-Immune Biotech and Miltenyi Biotec, along with the acquisition of GammaDelta Therapeutics and Maverick Therapeutics to its portfolio has considerably strengthened its position in R&D department. Around two years back, it also acquired Maverick’s renowned T-cell engager COBRA™ manufacturing platform.

     a) R&D and Pre-clinical steps

The cellular composition and immunophenotype of the administered CART cells play a crucial role in therapeutic success.

     b) Clinical developments: Phase I and Phase II

• TAK-981 is being tested to evaluate the safety, tolerability, preliminary efficacy and PK in advanced or metastatic solid tumors or relapsed/refractory hematologic malignancies.
• The study in Phase 2 is focused on dose expansion cohorts (cancer treatment expansions).

     c) Regulatory information

No drug has reached clinical trial phase III/IV, thus no FDA approval is granted.

2. Bellicum: The midsize pharma company has been actively developing treatments to target multiple cancers, such as pancreatic cancers and HER 2+ cancers.

     a) R&D and Pre-clinical steps

         GoCART – The company’s proprietary CAR-T platform to target solid tumors.

     b) Clinical developments: Phase I and Phase II

• Phase 1: Cell dose escalation studies to identify the maximum dose of BPX-601 administered with single or repeat doses of Rimiducid.
• Phase 2: Indication-specific dose expansion studies to assess the safety and pharmacodynamics (including BPX-601 persistence)

     c) Regulatory information

No drug has reached the clinical trial phase III/IV, thus no FDA approval granted.

The pharma SME is actively investing in engineered cell and gene therapies, mRNA therapeutics, antibodies, and small molecule immunomodulators to treat different types of tumors, including advanced melanoma, non-small cell lung cancer (NSCLC), head and neck, pancreatic, prostate, ovarian, and triple-negative breast cancer.

     a) R&D and Pre-clinical steps

The company designed combination therapy to target solid tumors. It employs CAR-T cell therapy directed against oncofetal antigen Claudin-6 and CLDN6-encoding CAR-T cell amplifying RNA vaccine (CARVac) enhancing transferred cell functionality.

      b) Clinical developments: Phase I and Phase II

• The Phase I/IIa is an FIH, open-label, multicenter, dose-escalation trial with expansion cohorts to evaluate the safety and preliminary efficacy of CLDN6CAR-T +/- CLDN6 RNA-LPX in patients with CLDN6-positive relapsed or refractory advanced solid tumors.

     c) Regulatory information

No drug has reached the clinical trial phase III/IV, thus no FDA approval was granted.

3. PERSON GEN THERAPEUTICS: The startup founded in 2010 has registered 13 CAR-T and CAR-NK clinical trials so far. The startup offers diverse platforms and a vibrant pipeline targeting multiple solid tumors.

     a) R&D and Pre-clinical steps

The company has multiple platforms centered around CAR.

• SAFEY UCAR PLATFORM
• CAR Structure Functional Verification Platform
• Automated CAR-T manufacturing platform
• Invivo CAR-T efficacy verification platform

     b) Clinical developments: Phase I and Phase II

• Anti-MUC1-CAR-T CELLS against gastric carcinoma, colorectal carcinoma, and malignant glioma.
• Another Trial Phase I/II Study of Anti-Mucin1 (MUC1) CAR T Cells for Patients With MUC1+ Advanced Refractory Solid Tumor

     c) Regulatory information

No drug has reached the clinical trial phase III/IV, thus no FDA approval has been granted. 

Recent Advancements in CAR-T Cell Therapy for Solid Tumors

Numerous enterprises have achieved significant progress around CAR-T cell therapy development by aiming to overcome challenges like tumor heterogeneity and the immunosuppressive tumor microenvironment. Few of the key developments by recognized organizations that strive to take cancer treatment to the next level are:

• Syn-Notch CAR Circuits

CAR-T cells have hit roadblocks in solid tumors that included the lack of highly tumor-specific antigens to target, elevating the possibility of life-threatening “on-target/off-tumor” toxicities, and problems with T cell entry into the solid tumor and persistent activity in suppressive tumor microenvironments.

SynNotch (Synthetic Notch) CAR T cells display superior control of tumor burden compared to T cells, constitutively expressing a CAR targeting the same antigens in mouse models of human mesothelioma and ovarian cancer.

Exhibit: synNotch Circuit

Researchers at the University of California achieved this by preventing CAR-mediated tonic signaling through synNotch-controlled expression, allowing T cells to maintain a long-lived memory and non-exhausted phenotype. Collectively, they have established ALPPL2 as a clinically viable cell therapy target, for multiple solid tumors and demonstrated the multifaceted therapeutic benefits of synNotch CAR-T cells.

• Anixa’s Chimeric Endocrine Receptor (CER)-T approach for Ovarian Cancers

Anixa’s novel CAR-T approach, known as “Follicle Stimulating Hormone Receptor (FSHR)-mediated CAR-T technology, recently got its patent approved in China. The CER-T is an autologous cell therapy comprising of engineered T-cells that target the follicle-stimulating hormone receptor FSHR in patients with Ovarian Epithelial cancer.

Exhibit: Anixa’s CER-T Approach

Design of CARs: The CAR constructs were designed using the signal peptide of murine CD8a, followed by a fusion of the full-length murine FSHb and CGa peptides linked by a glycine/serine spacer, followed by murine CD8a hinge and transmembrane domain and an intracellular fragment of murine 4-1BB and CD3z.

Rationale of the Study: The follicle-stimulating hormone (FSH) receptor is expressed on the cell surface of ovarian carcinomas of different histologic types, as well as on clear cell and mucinous tumors, which are particularly aggressive. Most importantly, no FSHR expression is found in nonovarian healthy tissues in adult women. Therefore, T cells redirected against FSHRþ tumor cells with full-length FSH represented a promising therapeutic alternative against a broad range of ovarian malignancies, with negligible toxicity even in the presence of cognate targets in tumor-free ovaries.

• Nanobody-based CARs

Approved CARs are based on monoclonal antibodies or SCFV (single-chain fragment variable) for target identification. Several problems are associated with SCFV based CAR’s ranging from losing their binding affinity post conversion from IGG, to difficulties in finding the most optimal linker and V-region orientation. The predominant usage of mouse-based SCFVs elicits the anti-immune response, with a tendency to aggregate along with their non-specific interactions.

Exhibit: Nanobody-based CARs

CAR nanobodies have thus been widely used as the antigen-binding domain of CAR-T owing to its small size, optimal stability, high affinity, and manufacturing feasibility.

Many companies, such as Bluebird Bio, Autolus, and the University of Pennsylvania, have actively developed Nanobody-based CAR constructs targeting solid tumors.

A clinical trial by LEGEND BIOTECH (NCT03090659) for multiple myeloma is currently in phase 2. Their construct comprises VHH incorporated into CAR.

Exemplary collaborations and partnerships in the last three years

• MUSC Hollings Cancer Center + Lowvelo

       

 

Researchers project started in MUSC Hollings Cancer Center focuses on studies aimed at reducing the side effects associated with CAR-T-cell therapy and providing better treatment options benefiting patients. The funding of the project is being supported by LOWVELO’s grant.

• Chimeric Therapeutics + WUXI ATC

           

Chimeric Therapeutics will leverage WuXi ATU’s end-to-end closed-loop CAR T process development, Good Manufacturing Practice (GMP) manufacturing, and testing platform to develop its drug CHM 2101.

• Transgene + PERSON GEN THERAPEUTICS

         

The strategic collaboration aims to evaluate the feasibility and efficacy of combination therapy associating PersonGen’s TAA06 CAR-T cell injection with intravenous (IV) administration of an armed oncolytic virus from Transgene’s Invir.IO™ platform for solid tumors, including pancreatic cancer and brain glioma.

Conclusion:

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