At the ASH conference, JUNO reported some things:
Juno Therapeutics Highlights Key Translational Insights with JCAR017 in Patients with DLBCL
"Today’s presentations suggest that the defined composition of JCAR017 supports a potential best-in-class clinical profile and helps to unlock key translational insights,” said Sunil Agarwal, M.D., Juno’s President of Research and Development. “These insights will help guide our next generation strategies to further improve durable responses.”
Tanya Siddiqi, M.D., of City of Hope National Medical Center presented insights from ASH Abstract #193, which analyzed patients enrolled in the diffuse large B-cell lymphoma (DLBCL) cohort of the TRANSCEND trial of JCAR017.
* Baseline patient characteristics, including high tumor burden and markers of inflammation, were associated with high CAR T cell expansion and increased rates of cytokine release syndrome (CRS) and neurotoxicity (NT).
* Data showed an approximately 8-fold increased risk for CRS and NT in patients with high baseline tumor burden.
*Baseline markers of inflammation were associated with more durable responses; with respect to tumor burden the association was less pronounced.
*In a separate analysis, Howard Stern, M.D., Ph.D. of Juno Therapeutics, presented findings from ASH Abstract #194, examining JCAR017 infiltration into tumor tissue and exploring potential mechanisms of resistance and relapse. Results showed that JCAR017 CD4 and CD8 CAR T cells infiltrated tumors post-treatment. CAR T cell infiltration trended higher in patients who achieved a response. At disease progression, CAR T cells were rare or absent in tumor tissue despite the presence of CD19 and persistence of peripheral blood CAR T cells in most patients. There does not yet appear to be a singular resistance pathway upregulated in the tumor at the time of progression, but well-known pathways such as PD-L1 and IDO were upregulated in different patients. These data suggest that combinations with other immunotherapies may be beneficial to further improve outcomes with JCAR017 therapy. Juno and Celgene are conducting an ongoing combination trial with JCAR017 and durvalumab, an anti-PD-L1 antibody.
Here is the link to poster #193:
Here are the RESULT and CONCLUSION of the poster:
As of May 7, 2017, 55 pts in the DLBCL cohort were evaluable for safety and 54 pts for efficacy. Four MCL pts were also evaluated for safety. Blood samples were collected at various time points per study protocol and evaluated for PK, PD, and cytokine levels. In the 59 pts evaluable for safety, CRS developed in 32% (30% Gr 1-2, 0% Gr 3, 2% Gr 4); NT was observed in 20% (5% Gr 1-2, 10% Gr 3, 5% Gr 4). Dose level did not correlate with CRS or NT (p=0.565 and p=1.00, respectively). Pt factors that correlate with any grade CRS and NT were poorer performance status [e.g. ECOG PS2] (p=0.03) and higher disease burden (p <0.05) as measured by the sum of the products of diameters [SPD] on imaging. Pre-CAR T cell clinical labs and cytokines associated with the occurrence of any grade NT were higher serum LDH, ferritin, and CRP, and higher plasma IL-6, IL-8, IL-10, TNF-a, IFN-a2, MCP-1, and MIP-1ß (p<0.05 for each). Higher pre-CAR T infusion plasma IL-8, IL-10, and CXCL10 were also associated with Gr 3-4 NT (p<0.05 for each).
Of the 54 pts [pts means patients] in the DLBCL cohort evaluable for efficacy, 76% achieved best overall response of CR/PR [CR=complete response, PR=partial response]; 51% remained in CR/PR at month 3. Higher ECOG scores and DLBCL transformed from CLL or MZL correlated with lower durable response at month 3 (p=0.02 for both). Pre-CAR T cell analytes associated with best ORR included lower values of ferritin, LDH, CXCL10, G-CSF, and IL-10, and those associated with durable response at 3 months were lower ferritin, CRP, LDH, CXCL10, IL-8, IL-10, IL-15, MCP-1, MIP-1ß, TNF-a, and higher pre-CAR T cell hemoglobin and albumin (p<0.05 for each).
Characterization of apheresis and drug product composition is underway; correlations with clinical attributes will be presented. Preliminary analyses suggest T cell memory subsets and T cell functionality may correlate with clinical outcomes.
Preliminary analysis has identified baseline patient characteristics, including inflammatory state and high tumor burden prior to treatment, as a means to identify patients at risk for increased toxicity following administration of JCAR017. Low tumor burden and low inflammatory state appear associated with improved toxicity profile and better durability of response. These preliminary data suggest that treating pts earlier in their course of therapy, or using a panel of clinical and laboratory biomarkers to risk stratify patients for potential early intervention, is feasible and may mitigate risk of toxicity and potentially improve durability of response.
Chris: if Juno can treat patients earlier in the course of the disease then the target market is increased (and if there is clinical benefit it also helps the patient).
Here is the link to poster #194:
JCAR017 is a CD19-directed 4-1BB CAR T-cell product administered in a defined composition at a precise dose of CD8 and CD4 CAR T cells. TRANSCEND NHL 001 is the first multicenter phase 1 trial of JCAR017 in R/R B-cell NHL (NCT02631044). Interim results (Abramson, 14-ICML 2017) demonstrated high complete response rates and low incidence of cytokine release syndrome (CRS) and neurotoxicity (NT). Tumor cell density, T cell density and detection of known immunosuppressive pathways were assessed retrospectively in tumor biopsies from TRANSCEND patients to examine relationships with clinical efficacy, CAR T PK, and safety endpoints.
Pretreatment tumors had varying cellular compositions: tumor cells (median: 77%; range 5 - 96%), CD4+ cells (0.90%; 0.02-15%), and CD8+ cells (1.5%; 0-23%). Preliminary data showed patients with a CR or PR at month 3 had a higher percentage of endogenous CD4+ cells in pretreatment tumors than those with a PD (CR, PR median: 7.9%; PD median: 0.38%; p < 0.0001). Percentages of CD8+ cells in pretreatment tumors did not differ between month 3 response groups (CR, PR median: 1.9%; PD median: 0.47%; p = 0.6496).
Following JCAR017 therapy, CAR T cells infiltrated the tumor and comprised up to 22% of cells. The level of tumor infiltration trended higher in patients achieving a CR (median: 3.9%) or PR (median: 1.1%) compared to those with a BOR of SD, PD (median: 0.51%). Although both CD4+ and CD8+ CAR T cells were able to infiltrate the tumor area, patients with a CR had a higher ratio of CAR T cells that were CD8+ (as compared to CD4+) than those with a BOR of SD or PD (CR median: 0.83; SD,PD median: 0.14; p = 0.0097).
Comparing matched pre- and post-treatment biopsies, patients achieving a BOR of CR or PR trended toward having a larger increase in CD8+ cells (CAR T and non-CAR T) in tumors as compared to patients achieving a BOR of SD or PD (CR, PR median change: +5.3%; SD, PD median change: +0.06%; p = 0.1225). Although expression of immunosuppressive factors varied widely among patients at pre-treatment (CD73 (median: 1.5%; range 0-42%), FOXP3 (0.10%; 0-1.5%), IDO (0.06%; 0-11%), CD163 (1.2%; 0-24%) and PD-L1 (0.16%; 0-56%)) and post-treatment (CD73 (1.6%; 0-53%), FOXP3 (0.09%; 0-4.3%), IDO (0.28%; 0-15%), CD163 (3.6%; 0-22%) and PD-L1 (3.3%; 0-65%)), increases in CD8+ cells in matched biopsies were associated with increases in IDO (R2 = 0.64) and PD-L1 (R2 = 0.61) expression.
The state of the tumor microenvironment prior to treatment may impact the efficacy of CAR T cell therapy. This initial analysis suggests durable response at month 3 is associated with higher levels of CD4+ cells in pretreatment tumors. Following JCAR017 therapy, CAR T cells, both CD4+ and CD8+, infiltrated the tumor and adjacent tissue. BOR was associated with an increase in CAR T cells. Increasing levels of CD8+ cells in the tumor were associated with increases in IDO and PD-L1, suggesting that therapies targeting these pathways may enhance JCAR017 activity. Detailed analyses are ongoing to examine additional associations of tumor burden, T cell infiltration, and immunosuppressive factor expression with clinical efficacy, PK and safety, and will be presented.
Chris: I think the data are very positive. We will see if the stock responds on Monday as this PR was issued over the weekend…