Durable Remissions in Children with Relapsed/Refractory ALL Treated with T Cells Engineered with a CD19-Targeted Chimeric Antigen Receptor (CTL019)
Authors: Grupp Stephan A. , Maude Shannon L , Shaw Pamela A , Aplenc Richard , Barrett David M. , Callahan Colleen , Lacey Simon F. , Levine Bruce L. , Melenhorst J Joseph , Motley Laura , Rheingold Susan R. , Teachey David T , Wood Patricia A. , Porter David , June Carl H. 
Published: October 2019

BACKGROUND

CARs combine a targeting antibody (scFv) domain with intracellular signaling domains. We have previously reported on CTL019 cells expressing an anti-CD19 CAR, which have resulted in up to 100,000x in vivo proliferation, durable anti-tumor activity, and prolonged persistence in pts with B cell tumors, including sustained CRs in adults and children with ALL (Grupp et al., NEJM 2013, Maude et al., NEJM 2014). We now report on outcomes and longer follow up of the first 53 pts with relapsed/refractory (r/r) ALL treated on our pilot trial in pediatric ALL.

METHODS

T cells were lentivirally transduced with a CAR composed of anti-CD19 scFv/4-1BB/CD3ζ, activated/expanded ex-vivo with anti-CD3/anti-CD28 beads, and then infused into children with r/r CD19+ ALL. 48/53 pts received lymphodepleting chemotherapy the week prior to CTL019 infusion. The targeted T cell dose range was 107 to 108 cells/kg with a transduction efficiency of 3.6-45%. T cells for manufacturing were collected from the pt regardless of prior SCT status, and not their allo donors.

RESULTS

We treated 53 children and young adults with CD19+ ALL, median age 11y, (4-24y). To assess disease burden after lymphodepleting chemotherapy, pts had BM aspirations performed 1D prior to 1st CTL019 infusion: 41/53 pts had detectable ALL while 12 were MRD(-). A median of 4.3x106 CTL019 cells/kg (1-17.4x106/kg) were infused over 1-2D (1 pt got cells over 3D). There were no infusional toxicities >gr2, although pts who developed fevers within 24h of infusion did not receive a planned 2nd infusion of CTL019 cells. 50 pts (94%) achieved a CR, including a patient with CD19+ T ALL, 3 did not respond. MRD measured by clinical flow cytometry was <0.01% at D28 in 45 responding pts and positive at 0.024%-1.1% in 5 pts, with 2 patients becoming negative by 3 mo with no further therapy. With median follow up 10.6 mo (1-39 mo), 29 pts have ongoing CR, with only 6 receiving subsequent treatment such as donor lymphocyte infusion or SCT, EFS is 70% at 6 mo (95% CI, 58-85%) and 45% at 12 mo (95% CI, 31-66%), RFS is 72% at 6 mo (95% CI, 59-87%) and 44% at 12 mo (95% CI, 30-65%), and OS is 78% at 12 mo (95% CI, 67-91%). CTL019 was detected by qPCR in the CSF of 46/47 pts and 4 pts with CNS2a ALL experienced a CR in CSF. 20 pts with a CR at 1 mo have subsequently relapsed, with 3 relapses occurring after subsequent therapy (i.e. SCT) and 13 with CD19(-) blasts. 4/5 pts previously refractory to CD19-directed blinatumomab went into CR with CTL019, 3 subsequently relapsed with CD19(-) disease.

All but 5 (90%) of pts developed grade 1-4 cytokine release syndrome (CRS) at peak T cell expansion. Detailed cytokine analysis showed marked increases of IL6 and IFNγ (both up to 1000x), and IL2R. Treatment for CRS was required for hemodynamic or respiratory instability in 28% of patients and was reversed in all cases with the IL6-receptor antagonist tocilizumab, together with short courses of corticosteroids in 9 pts. Although T cells collected from the 35 pts who had relapsed after allo SCT were median 100% donor origin, no GVHD has been seen. Grade 4 CRS was associated with high disease burden prior to infusion and with elevations in IL-6, ferritin (suggesting macrophage activation syndrome) and C reactive protein after infusion. Persistence of CTL019 cells can be detected by flow cytometry and/or QPCR, and results in the pharmacodynamic marker of CTL019 function, B cell aplasia, which continued for 3-39 months after infusion in pts with ongoing responses. B cell aplasia has been treated with IVIg without significant infectious complications.

CONCLUSIONS:

CTL019 cells can undergo robust in vivo expansion and can persist for 3 years or longer in children and young adults with r/r ALL, allowing for the possibility of long-term disease control without subsequent therapy such as SCT. This approach also has promise as salvage therapy for patients who relapse after allo SCT with a low risk of GVHD. CTL019 therapy is associated with a significant CRS that responds rapidly to IL-6-targeted anti-cytokine treatment. CTL019 cells can induce potent and durable responses for patients with r/r ALL; however, recurrence with cells that have lost CD19 is an important mechanism of CTL019 resistance. Rapid loss of CTL019 cells (prior to 3 months) is associated with a high risk of CD19+ relapse. CTL019 therapy has received Breakthrough Therapy designation from the FDA in pediatric and adult ALL, and phase 2 multicenter registration trials are well underway.

Disclosures

Grupp: Novartis: Consultancy, Research Funding. Maude:Novartis: Consultancy, Research Funding. Shaw:Novartis: Research Funding. Aplenc:Sigma Tau: Consultancy. Lacey:Novartis: Research Funding. Levine:Novartis: Patents & Royalties, Research Funding. Melenhorst:Novartis: Research Funding. Rheingold:Novartis: Consultancy; Endo: Other: Husband's employer, has equity interest. Teachey:Novartis: Research Funding. Wood:Novartis Pharmaceuticals Corporation: Employment. Porter:Novartis: Other: IP interest, Research Funding; Genentech: Other: Spouse employment. June:University of Pennsylvania: Patents & Royalties: financial interests due to intellectual property and patents in the field of cell and gene therapy. Conflicts of interest are managed in accordance with University of Pennsylvania policy and oversight; Novartis: Research Funding.