B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA CASE
- initial remission w/ chemo but quickly followed by skin and marrow relapse <- this is unusual/aggressive
- blinatumumab and inotuzumab w/o response
- leukemic lesions in skin
- (CAR)T-cell targeting CD-19 and CD-22 with refractory/relapsed B-cell lymphoma or ALL
- relapses long-term outcomes are 10% of event-free probability (generalized badness outcome?)
- rec’d lymphodepletion the followed by CAR T cells = day 0
- Day+4 he developed hypoxemia req’ing HFNC c/w Grade 3 CRS
- rec’d tocilizumab 8mg/kg x1 and dexamethasone 10mg x1
- this pt case developed CRS 2/2 large population of the CAR T cells (see pic below) where 92% of his cells were CAR T cells:
rituximab targets CD-20
- naked antibody targeting CD-20
AB-DRUG CONJUGATES IS THE NEW METHOD
- inotuzumab approved for ALL
- links anti-CD-22 Ab to chemotx
- blinatumomab
- one side CD-3 binds to T-cell; the other side binds CD-19 on surface of B-ALL
drug is the mainstay -> the problem is that remission is not durable
(CAR)T-CELL
- living therapy of the pt’s own immunity
- durable
- pt’s own T-cells usually
- engineered to recognize tumor Ag of interest
- different than BMT since that is taking someone else’s immunity and using for the pt
- T-cell’s req ag presentation to get activated
- (CAR)T-cells have receptor specific for the tumor ag of interest
- most commonly they’re CD-19 for B-cell malignancies
- the CAR can then recognize the tumor cell
- then, the CAR T cell multiplies, releasing cytokines leading to tumor apoptosis
- CAR are living therapy; the CAR can live and persist in the body, continuing to provide ongoing assassination of tumors
STEPS TO CAR T CELL THERAPY
- removal of T cells via apheresis
- T cells are engineered to express the CAR <- 2-6 weeks sometimes for the cells to grow
- infusion of the T cells into the pt
TRIALS FOR CAR T-CELLS IN ALL AND DLBCL
- Tisagenlecleucel is anti-CD19 chimeric antigen receptor
- Maude N Engl J Med 2018
- 2017 was the first lay press for ALL CAR T cell for pediatrics; then, followed FDA approval to age of 26 for diffuse large B-cell lymphoma
CYTOKINE RELEASE SYNDROME (CRS)
- hallmark of CAR therapy
- supraphysiologic response following immunotherapy
- hypotension
- fever
- capillary leak
- the peak of CAR T cells after infusion is approx D+7; this correlates with the peak of the inflammatory cytokines and markers (also, D+7)
- Grade 1 = supportive care
- Grade 2 = tocilizumab -> IL-6 antagonist FDA approved in 2017 for the treatment of CAR T associated CRS
- Grade 3 = tocilizumab + steroids (typically, dexamethasone 10mg q6) and alert ICU
- Grade 4 = methylprednisolone 1g x3
PROBLEMS WITH TOCILIZUMAB/IL-6
- there’s some areas of the body w/o IL-6 receptors (e.g., the brain)
- potential for the body to upregulate the IL-6 in the brain causing more severe picture
ANAKINRA/IL-1 ANTAGONIST
- FDA indication currently is rheumatoid arthritis
SILTUXIMAB/IL-6 ANTIBODY
- FDA indication is Castleman’s disease
ADVERSE REACTIONS FROM CAR T CELLS/THE IMMUNE EFFECTOR CELLS ASSOCIATED NEUROTOXICITY (ICANS)
- generally, encephalopathy and delirium, HA, sleep disorder
- Stanford approach is multi-disciplinary
- generally, the only intervention other than anti-IL drugs is steroids
