Immuno-gene therapeutics are transforming the therapeutic landscape of hematological malignancies. The recent approvals of two chimeric antigen receptor (CAR) T-cell therapies—tisagenlecleucel (marketed as Kymriah™) and axicabtagene ciloleucel (marketed as Yescarta™)—mark the beginning of the next revolution in cancer treatment. However, along with demonstrated efficacy in hematologic malignancies, CAR T-cells have the capacity to elicit serious toxicities.
Safety considerations related to CAR T-cells may impact both trial design and trial management, as the adverse events (AEs) associated with immuno-oncology agents differ from those associated with cytotoxic therapies. Consequently, anticipating, preventing and managing toxicity is a key component of clinical studies involving CAR T-cells.
Toxicities Associated with CAR T-Cell Therapies
AEs following T-cell-based therapies vary widely and may be immediate, delayed, mild, or severe. In some cases, the toxicities may persist for the lifespan of the genetically modified T-cell. CAR T-cell therapies have clear associations with serious toxicity. To date, cytokine release syndrome (CRS) is the most prevalent AE following CAR T-cell infusion. CRS can range in severity from low-grade constitutional symptoms to life-threatening multi-organ dysfunction. In rare cases, CRS can evolve into hemophagocytic lymphohistiocytosis (HLH) and it has been linked to two reported deaths in clinical trials. The second most common AE is CAR T-cell-related encephalopathy syndrome (CRES). Combination studies with other IO therapies could potentially increase toxicity in terms of both severity and range of AEs.
Figure 1. Adverse Events of Special Interest with Immuno-gene Therapeutics
Designing a CAR T study with Safety in Mind
Regular safety review meetings and Data Safety & Monitoring (DSM) are required for any study involving CAR T, and adjudication of dose-limiting toxicities (DLTs) may be considered.
In addition, the following should be clearly defined in the study protocol:
- Prophylactic measures
- Management and dose adjustments of other medication
- Permissible concomitant medications and supportive care
- Any immediately reportable AEs
- What does not need to be reported, e.g., progression of disease
To overcome safety challenges, it is also important to consider variables in the safety profile, including:
- Concomitant medications
- Disease being studied, prior lines of therapy, and disease burden
- CAR design and production and amplification of the CAR T-cell
- Patient pre-conditioning and administered doses
Toxicity Management with CAR T-Cell Therapy
Advancements in CAR T, such as integration of genetic constructs containing ‘safety (suicide) switches’ or ‘elimination genes’ and ‘remote-controlled’ CARs, may help to limit toxicities. Suicide switches and elimination genes are designed to eliminate target CAR T-cells when life-threatening toxicities develop. Remote-controlled CARs include an inducible gene-regulatory system that enables controlled expression.
Recently, the CAR-T-cell-therapy-associated TOXicity (CARTOX) Working Group developed a set of recommendations for monitoring, grading and managing toxicities in patients treated with CAR T therapy, and these recommendations should inform a patient’s schedule within a protocol design.
These recommendations suggest the following procedures before and during CAR T-cell infusion:4
- Baseline brain MRI to rule out any central nervous system disease
- Central venous access
- Cardiac monitoring by telemetry beginning on the day of CAR T-cell infusion and continuing until CRS resolves
- Tumor lysis precautions for patients with bulky tumors
- Consideration of seizure prophylaxis for therapies known to cause CRES
- Hospitalization for at least seven days after CAR T-cell infusion
Patient monitoring after CAR T-cell infusion should include:4
- Vital signs every four hours, along with close monitoring of oral and intravenous fluid input and urine output and daily measurement of body weight
- Daily review and physical examination
- Daily blood counts, complete metabolic profiling, and coagulation profiling
- Daily C-reactive protein and ferritin levels
- Assessment and grading of CRS twice a day, and whenever the patient’s status changes
- Assessment and grading of CRES using the CAR-TOX 10-point neurological assessment (CARTOX-10) every eight hours
- Maintenance intravenous fluids with normal saline to ensure adequate hydration
Figure 2. Grading of Cytokine Release Syndrome
Adapted from Lee DW, et al.5 ALT, alanine aminotransferase; AST, aspartate aminotransferase; FiO2, fraction of inspired oxygen; GI, gastrointestinal; IV, intravenous; SaO2, arterial oxygen saturation.
*Grade 1 CRS can manifest as fever and/or grade 1 organ toxicity.
‡For grades 2, 3, or 4 CRS, any one of the criteria other than fever is sufficient.
§High-dose vasopressors are defined in Lee DW, et al.5
||Grading of organ toxicities is performed according to Common Terminology Criteria for Adverse Events, version 4.03.
CARTOX-10 involves asking a patient to:4
- Name the year, month, city, hospital and president or prime minister of their home country (5 points)
- Name three nearby objects (3 points)
- Write a standard sentence (1 point)
- Count backwards from 100 by tens (1 point)
Every member of the care team and investigative site staff needs to be trained to recognize the unique toxicities of CAR T-cell therapies and be able to act accordingly. Accurate assessment and prompt, appropriate management of toxicities can help mitigate adverse outcomes, maximizing the benefit of adoptive T-cell therapies while minimizing the risk of life-threatening complications.
Watch our webinar to learn more about planning and operationalizing clinical studies of gene therapy technologies in hemato-oncology.
 Bonifant CL, et al. Toxicity and management in CAR T-cell therapy. Mol Ther Oncolytics 2016;2:16011.
 Hartmann J, et al. Clinical development of CAR T-cells—challenges and opportunities in translating novel innovative treatment concepts. EMBO Mol med 2017;9(9):1183-1197.
 Schuster SJ, et al. American Society of Hematology (ASH) Annual Meeting 2017: Abstract 577.
 Neelapu SS, et al. Toxicity management after chimeric antigen receptor T cell therapy: one size does not fit all. Nat Rev Clin Oncol 2018 Feb 13. Epub 2018 Feb 13.
 Lee DW, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood 2014;124:188-195.