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Insights on Cell Therapy From IO360



Executive Summary


  • IO360 underscored the importance of the starting cell type, as the overall consensus of the superior cell type was the potent and specific T cell vs. the better controlled / safer option of the NK cell; presentations also emphasized the advantages the naïve T cell phenotype (Tnaive) / stem memory T cells (Tscm) confer in in vivo proliferation, potency, and persistence

  • Current cell therapy hurdles are centered around exerting therapeutic efficacy in the solid tumor setting, minimizing associated toxicities, and resolving operational obstacles such as manufacturing complexity

  • Genome engineering technologies remain a critical component in ensuring a consistent and well-characterized cell therapy product with minimal off-target / off-tumor toxicities

  • Innovations to address remaining hurdles include “armoring” cells with enhanced cytokine support for enhanced persistence and functionality, knocking out expression of alloreactive components, and circumventing T cell exhaustion in the TME (e.g., via PD-1 knockout)

  • Preliminary clinical data are beginning to demonstrate proof-of-concept for strategies such as cytokine armoring, and use of specific T cell subtypes such as γδ T cells and naïve T cells have demonstrated improved clinical outcomes

  • Manufacturing innovations to address operational obstacles focused on reducing ex vivo culture time, using nonviral gene delivery methods, and engineering in vivo CAR-T


 

Key Theme: Cell Type Matters

T cells emerged as the marginally superior cell type in the black and white debate on T vs. NK cell superiority, as most patients were cited to prefer a robust and complete response with short-term toxicities (T cells) than a less efficacious therapy with a better safety profile (NK cells)



The naïve T cell phenotype was highlighted across multiple programs to exhibit reduced T cell exhaustion, greater in vivo proliferation, and correlation with positive clinical outcomes

  • Novartis’ T-Charge™ platform is cited to maintain naïve features of T cells for greater potency

  • BMS’ NEX T platform aims to preserve T cell stemness for CAR-T products, for greater expansion potential, more potent product, and increased manufacturing efficiency

  • Patients with better clinical response to CAR-T therapy showed a shift toward stem memory T cells (Tscm) and T-naïve phenotype in CD4 and CD8 T cells

iPSCs have strong potential in the allogeneic setting, as stated in multiple presentations


 

Remaining Challenges in Cell Therapy

  • Hurdles to achieving efficacy in the solid tumor setting include efficient cell trafficking, infiltration, persistence, and T cell exhaustion in the immunosuppressive TME

  • Safety concerns need to be managed

Auto: potential for high-grade toxicities (CRS, ICANS)

Allo: requirement for genome editing to avoid GvHD, and alloreactivity depletes the cell therapy graft

  • Logistical challenges due to long vein to vein times, variability in cell product, high costs due to manufacturing complexity, etc.

  • Defining the agents and duration of lymphodepletion


 


 

Learnings and Developments in Autologous Cell Therapies


[BMS]

Autologous CTx Clinical Learnings

  • BCMA antigen loss is not a major mechanism of disease progression, as only 4% (3/71 pts) experienced this after ide-cel treatment

  • 5% of CAR-T cells infiltrate the tumor, creating inflammation, resulting in higher response to liso-cel

Future Directions:

  • The NEX T platform develops cell therapy candidates that have a less differentiated CD8 T cell phenotype, for greater expansion potential, more potent product, and increased manufacturing efficiency

  • BMS has a strategic collaboration with Century for iPSC-derived CAR for MM and AML

  • GPRC5D is a novel target in MM and shows expression independent of BCMA

  • BMS is currently actively enrolling patients in a multi-center trial in the US for GPR5CD-targeted cell therapy


[Novartis]

T-Charge™ Preliminary Clinical Results

  • Autologous CD19 CAR-T (YTB323) and BCMA CAR-T (PHE885) in Phase 1 trials were developed through the T-Charge™ platform

YTB323 (CD19 CAR-T)

  • Shown to have promising efficacy of 63% CR across all dose levels, and 73% CR at Dose Level 2 of 12.5M cells

  • YTB323 showed robust in vivo expansion at a 25-fold lower dose, comparable to the higher end of Kymriah expansion in DLBCL pts

  • PHE885 (BCMA CAR-T)

  • 53% (8/15 pts) ORR at 3.5 months median follow-up

  • PHE885 exerted a deep level of response as 34% (2/6 pts) were MRD-negative at 3 months follow-up


 

T-Cell Based Therapy Insights


[Lumicks] T Cell Binding Avidity vs. Binding Affinity


Binding avidity is defined as the overall strength of interactions between the diversity of receptor-ligand pairs at the cell surface

  • Optimizing binding avidity is crucial to developing CAR/TCR-T therapies that are effective in tumors with low antigen density

  • Cellular avidity correlates with in vivo persistence as shown in KRAS G12D-specific TCRs

  • Mice studies showed CAR-T cells with highest avidity correlated with doubled survival

  • Intermediate avidity was shown to have minimized on-target, off-tumor toxicity

Binding affinity is defined as the strength of an interaction between a ligand and receptor

  • Binding affinity has lower impact on T cell function

  • Correlation of binding affinity with T cell function is a bell-shaped curve; after a threshold affinity, there is decreasing effect on T cell function


[Adaptive] Antigen-Specific TCR Identification


The multiplexed assay for identification of T cell receptor antigen specificity (MIRA) platform is more sensitive at detecting TCR clonotypes than the ELISPOT assay

  • Peptide-based MIRA uses peptide antigen pools (which can be derived from patient samples) to stimulate PBMCs; T cells activated by specific peptide pools are then sequenced

  • Transgene-based MIRA identifies neoantigen-specific TCRs that recognize endogenously processed antigens

Targeting neoantigens was highlighted as a promising strategy to develop TCR-T cell based therapies



 

Innovations In Cell Therapy Manufacturing


  • Reducing ex vivo culture duration improves the anti-leukemic activity of CAR-T

Ex: Rapid manufacturing of non-activated CD19 CAR-T through a 1-day expansion process was able to induce potent and durable remission of ALL at low doses

  • Lipid nanoparticle (LNP) / non-viral cargo delivery is a potential option to edit CAR-T cells

Ex: Intellia’s NTLA-5001 uses ex vivo gene editing by LNPs, requiring no electroporation

Ex: Precigen’s PRGN-3006 and PRGN-3007 use non-viral gene delivery via electroporation to co-express ROR1 CAR, membrane-bound IL15, and kill switch overnight

  • Engineering in vivo CAR-T can be explored to reduce vein to vein time

Ex: Sana is developing in vivo CARs in macaques, using CD8 or CD8-targeted fusosomes with CD20 CAR

  • T cell quality can be improved by BET bromodomain inhibition, which can restore function of exhausted T cells, as seen in CLL patients

  • Redundancy is key in manufacturing; smaller facilities with fewer staff and less equipment are more susceptible to errors





For Details on Axiom’s Capabilities, Contact:

Hafiz Sikder – hs@axiomhcs.com



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