CAR-T cell Therapy and T cell Engagers

Chelsie Sievers

Michael Kaminski

Background 

  • Chimeric antigen receptor T cells (CAR-T): collected from the pt and genetically modified to contain receptor with: targeting element (usually single chain variable fragment-scFv), a transmembrane domain, and internal signaling (CD3) and costimulatory (CD28 or 4-1BB) domains
    • CAR-Ts are infused into patient and recognize tumor via new receptor >> T cell killing and proliferation>>T cells persist in host
  • Bi-specific T cell Antibodies (BiAbs): engineered Abs, one domain binds CD3, the other binds a tumor antigen >> juxtaposes killer T cells with tumor >> killing. Bi-specific antibodies have 4 distinct peptides (2x heavy chains and 2x light chains)
  • Bi-specific T cell Engagers (BiTEs): CD3 binding domain and a tumor antigen binding domain >> juxtaposes T cells with tumor cells >> killing. The two domains are made from a single polypeptide, no Fc domain >> smaller and rapidly cleared by the kidneys, necessitating continuous infusions

FDA Approved CAR Ts 

  • Multiple Myeloma, anti-BCMA: Abecma/idecabtagene vicleucel, Carvykti/ciltacabtagene autoleucel
  • Large B-Cell Lymphoma, anti-CD19: Breyanzi/lisocabtagene maraleucel, Kymriah/tisagenlecleucel, Tecartus/brexucabtagene autoleucel, Yescarta/axicabtagene ciloleucel
  • Follicular Lymphoma, anti-CD19: Yescarta/axicabtagene ciloleucel
  • Mantle Cell Lymphoma, anti-CD19: Tecartus/brexucabtagene autoleucel
  • Adult B-cell ALL, anti-CD19: Tecartus/brexucabtagene autoleucel

FDA Approved Bi-Specific T Cell Antibodies/Engagers 

  • Multiple Myeloma: Tecvayli/teclistamab-cqyv (CD3 x BCMA BiAb); Talvey/talquetamab-tgvs (CD3 x GPRC5D [a GPCR] BiAb); Elrexfio/elranatamab-bcmm (CD3 x BCMA BiTE)
  • Adult B-cell ALL, anti-CD19: Blincyto/blinatumomab (CD3 x CD19 BiTE)
  • B-cell Lymphomas: Lunsumio/mosunetuzumab-axgb (CD3 x CD20 BiAb); Epkinly/epcoritamab-bysp (CD3 x CD20 BiAb); Columvi/glofitamab-gxbm (CD3 x CD20 BiAb)
  • NSCLC: Rybrevant/amivantamab-vmjw (CD3 x EGFR/MET BiAb)
  • SCLC: Imdelltra/tarlatamab-dlle (CD3 x DLL3 BiTE)
  • Uveal Melanoma: Kimmtrak/tebentafusp-tebn (CD3 x HLA-A*02:01/gp100 peptide BiTE)

Toxicities 

  • Cytokine Release Syndrome (CRS)
    • CAR T cells (or T cells activated by BiTE/BiAb) release massive amounts of cytokines/IFNg >> macrophages produce IL-6, IL-10, TNFa, higher risk for CAR-T compared to BiTE/BiAb and with bulkier disease
    • S/Sxs: days to weeks following infusion; fever, arthralgia/myalgia, hypotension, hypoxemia, SIRS response, capillary leak syndrome; end organ damage of any organ (CV, lung, liver, kidney, CNS)
    • Dx: monitor for ~7 days following CAR-T infusion; rule out infectious causes (RVP, CXR, sputum culture, Blood Cx, Urine Cx, GIPP)
    • ASTCT Grading for CAR-T CRS:
      • Grade 1: Fever >100.4, no hypotension or hypoxia
      • Grade 2: Fever > 100.4, hypotension NOT requiring pressors and/or hypoxia requiring < 6L NC
      • Grade 3: fever > 100.4, hypotension requiring one pressor and/or hypoxia requiring > 6L NC
      • Grade 4: fever > 100.4, hypotension requiring multiple pressors and/or hypoxia requiring positive pressure (BiPAP, intubation)
    • CTCAE v5.0 Grading for BiTE/BiAb CRS
      • Grade 1: Fever >100.4,
      • Grade 2: Fever > 100.4, hypotension responsive to fluids (no pressors) and/or hypoxia requiring < 40% FiO2
      • Grade 3: fever > 100.4, hypotension requiring one pressor and/or hypoxia requiring > 40% FiO2
      • Grade 4: fever > 100.4, life-threatening systemic symptoms
    • Tx:
      • CAR-T CRS:
        • Grade 1: APAP
        • Grade 2: ICU transfer, APAP +/- tocilizumab 8 mg/kg IV (max 800 mg, up to 3 doses in 24 hrs, 8 hrs apart)
        • Grade 3-4: ICU transfer, APAP, tocilizumab +/- steroids (Dexamethasone 10 mg IV q6h vs methylpred 1g/d) or together
      • BiTE/BiAb CRS: refer to package inserts for agent specific CRS management
        • Grade 1: APAP +/- temporarily interrupting infusion (discuss with fellow/attending)
        • Grade 2/3: agent specific, will be some combo of interrupting infusion, APAP, resuming at lower infusion rate
        • Grade 4: Stop infusion permanently, dexamethasone 8 mg IV q8h +/- tocilizumab
  • Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)
    • Pathophysiology: high systemic inflammation >> leaky BBB and cytokine diffusion into brain, maybe CAR-T trafficking into brain with local cytokine production
    • S/Sx: ~4-10 days post infusion, may be seen with CRS; altered consciousness, aphasia, impaired fine motor skills, seizures, elevated ICP Sxs like HA
    • ASTCT ICANS Grading based on AAO to year, month, city, hospital (4 pts); naming 3 objects ie naming clock, pen, button (3 pts); follow simple commands ie “show me 2 fingers” (1 pt); ability to clearly write a sentence (1 pt); ability to count backwards from 10 (1 pt):
      • Grade 1: ICE 7-9
      • Grade 2: ICE 3-6
      • Grade 3: ICE 0-2
      • Grade 4: ICE 0, seizure, unarousable, or severe cerebral edema/increased ICP
    • Workup: q4 hr neuro checks unless Grade 2 or higher then ICU transfer for q1h neuro checks; neuro consult, ophtho consult for dilated fundo exam; CT head vs MRI brain wwo contrast; EEG
    • Tx:
      • Grade 1: Supportive
      • Grade 2-3: Dexamethasone 10 mg IV q6h
      • Grade 4: methylpred 1g IV q24h
      • ASMs per neurology, maybe levetiracetam for seizure PPX
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