4SCAR19 Chimeric Antigen Receptor-Modified T Cells As a Breakthrough Therapy for Highly Chemotherapy-Resistant Late-Stage B Cell Lymphoma Patients with Bulky Tumor Mass

Background: Chemo-resistant, advanced B cell lymphomas with bulky tumor are difficult to treat and often fatal. Recent studies have shown that CD19 chimeric antigen receptor-engineered T (CAR-T) cells can effectively treat B-cell malignancies. However, CAR-T therapy-associated adverse systemic responses including fever, tachycardia, profound hypotension, and respiratory distress, can be life-threatening. The toxicities of CAR-T infusion are directly correlated with tumor burden, disease sites and other complications during treatment. Therefore, highly individualized CAR-T therapy regimen is key to the success of such innovative treatment.

Patients and Methods: In this phase I/II multi-center CAR-T therapy trial, we have evaluated 13 patients (pts) with chemo-resistant B cell lymphomas, including 12 advanced diffuse large B cell lymphomas (DLBCL) and 1 Burkitt’s lymphoma, average age 37 (range 9-61), stage IIIA/IVB. Twelve of them had bulky tumor and met the criteria of high-risk by the second-line age-adjusted international prognostic index (sAAIPI) and were associated with the following co-morbidities: Aspergillus invasive fungal infection (IFI) pneumonia (2), drug-induced liver injury (2), pleural pericardial cavity effusion (2), hepatitis B (2), diabetes mellitus (1), gastrointestinal hemorrhage (1), deep venous thrombosis (1), and lung tumor argon-helium cryoablation surgery (1). Autologous T cells were apheresis collected and lentivirally transduced with a 4^th generation, apoptosis-inducible, safety-engineered CAR: CD19- scFv/CD28/CD137/CD27/CD3ζ-iCasp9 (4SCAR19). All pts received conditioning regimen of cyclophosphamide 250 mg/m²/d x3d, and fludarabine 30 mg/m²/d x3d, followed by 1 to 3 infusions of CAR-T cells in a dose range of 0.45- 4.59 x10⁶ cells/kg per infusion.  

Results: The lentiviral 4SCAR19 transduction efficiencies were in the range of 5-100%. Patient response did not always correlate with CAR gene transfer efficiencies, but instead, correlated better with the condition of the T cells. Eight pts have achieved complete tumor regression (CR) for 3 to 10 months, with stable CAR DNA copies of 0.1-0.4% in the blood. Three pts achieved dramatic tumor reduction but died from various causes including: intracranial hemorrhage due to low platelet count, pre-existing ureteral obstruction/acute renal failure and cardiopulmonary complications, with or without severe cytokine release syndrome (CRS) at day 29, 28 and 66 after CAR-T infusion, respectively. Two pts died from progressive diseases.  Treatment toxicities included CRS with fever over 39^oC (9/13), massive hemorrhage of the alimentary tract (1/13) and severe myelo-suppression (3/13), which were correlated with increased plasma cytokines including IL-6 and IFN-γ.  The 120 day disease-free survival (DFS) rate is 53% (CI, 36-69%), and the 10 month overall survival probability is 55% (CI, 39-74%).

Conclusion and discussion: While 4SCAR19 T cells can relieve severe disease symptoms and obtain dramatic tumor control even in late-stage, highly chemo-resistant, bulky tumor-bearing pts, our studies suggest that in order to obtain favorable and durable clinical outcomes in the late-stage pts, the optimal timing for CAR-T engagement, a highly individualized chemo-regimen, and better clinical management for CRS and pre-existing health conditions are critical. While long-term follow-up and better understanding of the tumor genotype and immunobiology are needed, our study indicates that a highly experienced clinical management team is key to the success of CAR-T therapy for advanced B cell lymphomas.