Early intervention methods to prevent or ameliorate toxicity

Abstract

Provided are methods for preventing or ameliorating toxicity caused by or due to a therapy, such as an immunotherapy or a cell therapy, by pre-emptive or early administration toxicity-targeting agent(s). In some embodiments, the therapy is a cell therapy in which the cells generally express recombinant receptors such as chimeric receptors, e.g., chimeric antigen receptors (CARs) or other transgenic receptors such as T cell receptors (TCRs). Features of the methods, including the timing of the administration of the agents or treatments for toxicity, provide various advantages, such as lower toxicity while maintaining persistence and efficacy of the administered cells.

What is claimed is: 
     
         1 . A medicament for treating, preventing, delaying, or attenuating the development of severe cytokine release syndrome (CRS) in a subject to whom a therapy for treating a tumor or a cancer has been previously administered, the medicament comprising an agent,
 characterized in that the medicament is used such that said agent is administered to the subject at a time within 24 hours after the first sign of fever following initiation of administration of the therapy, and wherein the agent comprises tocilizumab and the therapy comprises a chimeric antigen receptor (CAR) T cell therapy.   
     
     
         2 . The medicament of  claim 1 , characterized in that the medicament is used such that the agent is administered within about 16 hours after the first sign of a fever following initiation of administration of the therapy. 
     
     
         3 . The medicament of  claim 1 , wherein the fever:
 a) is a sustained fever;   b) is a fever that is not reduced or not reduced by more than 1° C. after treatment with an antipyretic, and/or wherein the fever has not been reduced by more than 1° C., following treatment of the subject with an antipyretic;   c) comprises a temperature of at least or at least about 38.0° C.; and/or   d) comprises a temperature that is (i) between or between about 38.0° C. and 42.0° C.; or (ii) greater than or greater than about or is or is about 38.5° C.   
     
     
         4 . The medicament of  claim 1 , characterized in that the medicament is used such that the agent is administered less than five days after initiation of administration of the therapy. 
     
     
         5 . The medicament of  claim 1 , wherein the CAR T cell therapy comprises anti-CD19 CAR T cell therapy. 
     
     
         6 . The medicament of  claim 1 , characterized in that the medicament is used such that the tocilizumab is administered in a dosage amount of from or from about 1 mg/kg to 12 mg/kg. 
     
     
         7 . The medicament of  claim 1 , which is for use in combination with a second agent comprising dexamethasone. 
     
     
         8 . The medicament of  claim 1 , which is for use in combination with a second agent comprising dexamethasone, characterized in that the medicament is used such that the second agent is administered:
 (i) at a time that is within 7 days after initiation of administration of the therapy;   (ii) at a time that is within 24 hours after the first sign of hypotension following initiation of administration of the therapy;   (iii) at a time at which the subject exhibits grade 2 cytokine release syndrome (CRS) or within 24 hours after the subject exhibits a first sign of grade 2 CRS following initiation of administration of the therapy; and/or   (iv) at a time at which the subject exhibits grade 2 neurotoxicity or within 24 hours after the subject exhibits a first sign or symptom of grade 2 neurotoxicity following initiation of administration of the therapy.   
     
     
         9 . The medicament of  claim 8 , characterized in that the medicament is used such that the dexamethasone is administered within 24 hours after or contemporaneously with the first sign of hypotension following initiation of administration of the therapy, and/or such that the dexamethasone is administered simultaneously with initiation of a pressor therapy. 
     
     
         10 . The medicament of  claim 1 , wherein the subject has a disorder selected from a leukemia or a lymphoma.