CMN-008 (Armored CAR-CIK cells)

Armored Chimeric Antigen Receptor (CAR) modified Cytokine Induced Killer (CIK) cells

CMN-008 (Armored CAR-CIK cells)

pT4-CD19CAR-IL

Technology acquired from Memorial Sloan Kettering

  • CIK cells genetically modified using SB100X mRNA + pT4 vector encoding both CD19 CAR and IL-18
  • Referred to as ‘armored CAR’

Constructed a bicistronic vector encoding both CAR-CD19 and IL-18

  • The transposon inserted into the chromosome contains both genes (shown in red)
  • Ensures that all CAR+ cells are IL-18+

CMN-008 addresses the market concerns

Safety

  • IL-18 only secreted in the presence of CD19+ cells (no systemic toxicity observed)
  • Does not require lymphodepletion in animal models (game changer if same true for patients)
  • Suitable for outpatient usage and administration at community sites (allo product avoids complex autologous logistics)
  • Lower dose required for same efficacy in animal models

Efficacy

  • Increased anti-tumor activity
  • Increased in vivo expansion (unaffected by homeostatic cytokines)
  • Enhanced persistence and durability of responses (deeper and longer lasting B cell aplasia in animal models)
  • Recruits other types of immune cells for a more complete anti-tumor response (CD8+ , NK, NKT, dendritic cells)

Reduced lead time

  • Requires only a 17-day process (current autologous therapies have 3-4 week lead time)

Affordability will ease reimbursement issues

  • Streamlined manufacturing process and replacing retrovirus with Sleeping Beauty 100X greatly reduces COGS

Armored CAR technology works with CIK cells

Test article

test-article-graphic

Built-in safety – No IL-18 secretion without tumor cells present

Built-in safety – No IL-18 secretion without tumor cells present

IL-18 secreted only when stimulated with tumor cells

*REH cells: CD19+ tumor cell line

CMN-008 more than doubles the anti-tumor activity of CMN-005

CMN-008 more than doubles the anti-tumor activity of CMN-005

Enhanced functionality vs REH cells with IL-18 expression

Published data:
IL-18 CAR-T cells fully effective even without lymphodepletion

  • Standard CAR-T cells are not effective without lymphodepletion
  • Armored CAR-T cells are highly effective even without lymphodepletion (Top)
  • IL-18 is responsible for the enhanced activity since armored CAR-T cells are ineffective in IL-18 receptor knockout mice (Bottom)
syngeneic-lymphoma-model

Published data:
IL-18 CAR-T have improved properties

  • Armored CAR-T cells expand rapidly in vivo (Top right)
  • Armored CAR-T cells induce deeper and durable B cell aplasia i.e., anti-leukemia effect (Bottom right)
  • Armored CAR-T cells recruit other immune cells to the bone marrow (Below)
Cell frequency in the bone marrow
CAR T cell expansion
B cell aplasia

Cell Reports 23, 2130–2141, 2018