CD19-Targeted CAR T Cells in Haematologic malignancies

Speaker: Jae Park, MD / Memorial Sloan Kettering Cancer Center | Specialized in ALL CLL NHL

CD19-Targeted CAR T cells

Contents

• Ab + T cell receptor -> chimeric
• MHC presentation해서 보는게 아니라 Ab처럼 binding하지만 Action은 T cell
• 두개를 합친것. 어떻게 clinic에 사용할 것인가?
• Stable expression할 수 있다.

https://www.mskcc.org/blog/car-t-cell-therapy-growing-area-research

• Average 60%정도 replication하는 동안은 CAR expression.
• Tumor antigen을 CAR T Cell이 보게 되면서 죽이게 된다.
• Target selection
  • 가장 중요한 것.
  • Protein 등 - tumor specific target인 것이 중요하다.
  • 어떻게 하면 on-target, off-target toxicity를 줄일 수 있을까? off-target, off-target toxicity 줄여야함.
• CD19 and other B cell markers (Stem cells - mature B)
• Normal B cell -> not tumor specific함.
• Signal 1만 막아. Signal2 - CD28, 4-1BB, OX-40 | signal 2가 없으면 anergic - First gen CAR에서는 실패. 2nd gen CAR는 CD28, 4-1BB, OX40
• 3rd gen CAR에서는 임상에서 많이 사용되지는 않는다.

• Cell production - T cell expansion by dynabeads - 19-28z+ vector와 T cell을 섞어줌. 19-28z+ transduced T cells | CTCEF
• GVHD minimal risk
• ALL - CLL과 다르게 proliferation 빠르다.
• Relapsed ALL은 Px - poor
• Post-CAR T cell infusion
• No cure. 5년정도 F/U
• Clinical Trial
• 4/18 relapse
• Overall survival - relapse하긴 하나
• Murine - T cell - Flow cytometry통해서.
• cytokine release syndrome
• Tc 얼마나 last하는가는 key question
• 어느정도 lasting하는가? - NEJM 2014 - Maude
  • 소아라서 Quality가 다를 수 있는 확률이 있어.
• CRS - fever, hypotension, resp insufficiency - 7일정도
• Neurological changes - delirium, global encephalopathy, aphasia, seizure-like activities/seizure
• disease burden 많으면 severe CRS - correlation이 있다.
• CRP - IL-6 release 높아져.
  • Tocilizumab
    • humanized monoclonal antibody against the interleukin-6 receptor (IL-6R). Interleukin 6 (IL-6) is a cytokine that plays an important role in immune response and is implicated in the pathogenesis of many diseases, such as autoimmune diseases, multiple myeloma and prostate cancer.
  • Steroid

Summary

• High CR rates can be achieved in both adults and children with R/R B-ALL
• Durable response - no subsequent allo-SCT
• CRS - mc AE a/w CD19 CAR T cells - toci, steroid
• Neurotoxicity - difficult

Additional comments

• The hostile Tumor microinvironment
• Armored CARs
  • genetic modification - IL12, CD40L
  • PD-1 K/O할수도 있고..
• IL-12
  • IL-12 pro-inflammatory - IV infusion힘들어.
  • IL-12 secretion-> NK cells & Anergic TIL ->
• CD40L
  • Armored CD40L CAR

For the future

• Less cumbersome, 3rd party, 더 강한 Tc, solid tumor에서 적용,

Conclusions

• Autologous CD19-Targeted
• High response rate이지만 perfect하지 않음
• 왜 resistance일어나는지?
• CLL, ALL 다른점 무엇인지?
• heme malignancies-> applicability 있는지? solid tumor로 갈수 있을지?
• target selection

My Question

Dynabeads를 통해 polyclonal activation된 후 filter할 수 없나?

Questions

• Car T cell in CSF - Yes
• 41BB PD-1

Reference

• Park J. et al. ASH 2015, Abstract 682
• Efficacy and safety of CD19-targeted 19-28z CAR modified T cells in adult patients with relapsed or refractory B-ALL. Jae Hong Park MD http://meetinglibrary.asco.org/content/110503?media=vm