addition of nivolumab to anti-cd-19 car-t cells in patients with stable/progressive dlbcl at lymphodepletion

Conditions: B Cell Lymphoma

Summary: progression of dlbcl is the major obstacle for the success of chimeric antigen receptor-t cell (car-t) with approximately 60% of the patients relapsing in the first year, and 40% within 3 months, after infusion. while patient with dlbcl in partial response/complete response at lymphodepletion have a 1-year progression free survival (pfs) of 60-80%, those with stable disease/progressive disease at time of lymphodepletion have a dismal pfs of 20-30%. trials showed that better expansion of car-t cells, even in patients with a progressive disease, may overcome this grave prognosis and may result in better pfs

factors that may introduce resistance to car-t. in addition to the bulk of disease, include also expression of check point molecules that eventually interfere with the car-t action. the investigator, have recently shown (ebmt 2022, # lwp-03) a real-life data, that day +7 car-t concentration in patients with stable or progressive disease (sd/pd) at lymphodepletion segregates patients to those with high car-t blood concentrations that achieve a high cr/pr rate after car-t infusion ,those with 20-100 car-t cells/microl that achieve a lower cr/pr rate after car-t infusion, and those with \<20 cells/microl that achieve the lowest cr/pr rate after infusion. thus, the extent of car-t cell expansion on day 7 after treatment is a prognostic marker predicting response to treatment in this patient group. considering all these - patients with sd/pd at time of lymphodepletion, and specifically those with lower car-t blood concentrations on day +7 are at a very high risk for early disease progression after car-t infusion and, as such, there is an urgent unmet medical need to improve their outcomes. addition of anti pd-1 to patients with low expansion of car-t cells may overcome the inhibitory effect of pd-1 expression and may result in a better function of the car-t and eventually tumor suppression. nivolumab is a human monoclonal antibody targeting (programmed death-1 ) pd-1, a negative regulatory molecule expressed by activated t and b lymphocytes. anti pd-1 treatment has been administered as a single dose or repeated administration in different time points during car-t cell therapy. these studies showed that this treatment is safe, well tolerated and does not result in increased car-t associated toxicities, mainly cytokine release syndrome(crs) and immune effector cell associated neurotoxicity(icans). the optimal time window to administer these agents for achieving safety and efficacy is not determined.

Eligibility criteria:
inclusion criteria: 1. participant must be at least 18 years of age inclusive, at the time of signing the informed consent. 2. dlbcl treated with car-t targeting cd19 (tisagenlecleucel, axicabtagene ciloleucel, or lisocabtagene maraleucel) 3. pd/sd by pet-ct on the day of lymphodepletion 4. capable of giving signed informed consent 5. eastern cooperative oncology group (ecog) performance status of 0-2 6. no active crs or icans at time of nivolumab administration exclusion criteria: 1. hypersensitivity to checkpoints inhibitors 2. crs grade 3 and above or icans any grade on days 0-5 following car-t 3. ast (aspartate transaminase) or alt (alanine transaminase) over 3 times the upper limit of normal (uln) or total bilirubin over 3 times uln 4. serum creatinine over 1.5 times uln or over 1.5 times baseline 5. history of or active autoimmune disease 6. uncontrolled seizure activity and/or clinically evident progressive encephalopathy 7. active diarrhea (more than 4 bowel movements per day) 8. clinically significant uncontrolled illness 9. active infection requiring antibiotics 10. known history of immunodeficiency virus (hiv) or hepatitis b or hepatitis c infection 11. other active malignancy 12. females only: pregnant or breastfeeding