Chimeric antigen receptor (CAR) T cells have demonstrated promising efficacy, particularly in hematologic malignancies. One challenge regarding CAR T cells in solid tumors is the immunosuppressive ...tumor microenvironment (TME), characterized by high levels of multiple inhibitory factors, including transforming growth factor (TGF)-β. We report results from an in-human phase 1 trial of castration-resistant, prostate cancer-directed CAR T cells armored with a dominant-negative TGF-β receptor (NCT03089203). Primary endpoints were safety and feasibility, while secondary objectives included assessment of CAR T cell distribution, bioactivity and disease response. All prespecified endpoints were met. Eighteen patients enrolled, and 13 subjects received therapy across four dose levels. Five of the 13 patients developed grade ≥2 cytokine release syndrome (CRS), including one patient who experienced a marked clonal CAR T cell expansion, >98% reduction in prostate-specific antigen (PSA) and death following grade 4 CRS with concurrent sepsis. Acute increases in inflammatory cytokines correlated with manageable high-grade CRS events. Three additional patients achieved a PSA reduction of ≥30%, with CAR T cell failure accompanied by upregulation of multiple TME-localized inhibitory molecules following adoptive cell transfer. CAR T cell kinetics revealed expansion in blood and tumor trafficking. Thus, clinical application of TGF-β-resistant CAR T cells is feasible and generally safe. Future studies should use superior multipronged approaches against the TME to improve outcomes.
Background: Cellular therapy using anti-CD19 autologous chimeric antigen receptor modified T (CART19) cells demonstrates promising outcomes in several hematologic malignancies of B-cell origin, but ...this therapy has not been studied in HL patients (pts). While neoplastic HL Reed-Sternberg (HRS) cells are considered CD19 negative, circulating CD19 positive clonal HRS cell precursors and CD19 positive reactive cells within the HRS tumor microenvironment represent potential therapeutic targets for CART19 in HL.
Methods: We designed companion pediatric (NCT02624258) and adult (NCT02277522) open-label pilot studies to estimate the feasibility, safety, and efficacy of CART19 cell infusions in pts with relapsed/refractory HL lacking curative treatment options. To allow transient CD19 targeting and limit the window for acute toxicity and B cell aplasia, we used autologous T-cells electroporated with mRNA encoding chimeric anti-CD19 immunoreceptor scFv (RNA CART19) cells in lieu of permanently modified cells engineered by viral transduction. The scFv is derived from a murine monoclonal antibody. Following pheresis and manufacturing of RNA CART19 cells, pts undergo up to 6 infusions of 8x105-1.5x106 RNA CART19 cells/kg/dose for pts <80kg and 1x108 RNA CART19 cells/dose (±20%) for pts ≥80kg. Intravenous cyclophosphamide (30mg/kg) is administered prior to the first and fourth infusion to enhance engraftment. Safety, response assessments (Cheson 2007 criteria), and ancillary studies are measured at defined time points. The primary objective is to describe manufacturing feasibility, safety, and persistence of RNA CART19 cells in HL. Secondary objectives are to estimate efficacy by overall response rates (ORR) and the effect of RNA CART19 on immune factors.
Results: To date, 5 pts have been enrolled and had RNA CART19 manufactured. Four pts were infused with RNA CART19 and are evaluable for toxicity/response. Characteristics of the 5 pts include: median age 24 years (range 21-42), 4 (80%) with stage IV, median number of previous therapies 5 (range 4-9), 4 (80%) had stem cell transplant (SCT): 3 had auto SCT, 1 had both auto and allo SCT. Three pts previously progressed on PD-1 inhibitor. All 5 pts underwent successful manufacturing of RNA CART19. One pt developed MDS prior to RNA CART19 infusions and was taken off study. Four patients who underwent RNA CART19 infusions were treated with cyclophosphamide as per protocol. The median number of infused CART19 cells/kg/dose was 1.5x106 (range 7.3x105 -1.5x106). Each patient (pt) received 6 infusions over 2 weeks. Using qRT-PCR, RNA CART19 was detected in 80% of peripheral blood samples drawn within 2 hours after each infusion (Figure 1). RNA CART19 was also detected in 20% of samples drawn immediately prior each infusion reflecting persistence of RNA CART19 from previous infusion at 48 or more hours ago. No pt had RNA CART19 detected by Day (D) 21. There were no study related deaths or grade (G) 3/4 non-hematologic toxicities. Most common G1/2 toxicities at least possibly related to the RNA CART19 therapy occurring in > 1 pt included transient headache in 3 and insomnia in 2. There was no evidence of cytokine release syndrome or significant elevation in cytokines at any point. The ORR at D28 was 50%: 1 complete (CR) and 1 partial response (PR). One pt had stable disease (SD) and one pt had progressive disease (PD). The CR pt (#3) was noted to have persistent RNA CART19 cells in 3 samples drawn at about 48 hours after the prior infusion compared with the PD pt (#1) who had no RNA CART19 detected by this time point on any measurement. In 2 pts who responded (#3 and #4), number of CD19-positive B-cells by flow cytometry as % of total leukocytes declined by 50% on D28 when compared to baseline. There was no evidence of B cell aplasia. The pt in CR progressed at 3 months and the pt in PR was taken off study. As part of routine clinical care, the 2 responding pts (#3 and #4) are currently in CR on PD-1 inhibitor (one underwent auto SCT). The pt with SD is in PR on lenalidomide and the pt with PD died of disease progression.
Conclusion: Targeting CD19 positive cells with non-viral, RNA-electroporated, transiently expressed CART19 cells is a feasible and safe strategy in pts with relapsed/refractory HL. We saw encouraging responses, but these were short-lived. We are planning a study for HL pts utilizing virally transduced CART19 cells that are capable of in vivo expansion in combination with PD-1 inhibitors.
Display omitted
Svoboda:Merck: Research Funding; BMS: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Celgene: Research Funding; Kite: Consultancy; Pharmacyclics: Research Funding. Gill:Novartis Pharmaceuticals: Patents & Royalties, Research Funding. Grupp:Adaptimmune: Consultancy; University of Pennsylvania: Patents & Royalties; Jazz Pharmaceuticals: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Other: grant. Lacey:Novartis: Research Funding; Genentech: Honoraria. Melenhorst:Novartis: Research Funding. Mato:DTRM: Research Funding; AstraZeneca: Consultancy; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Regeneron: Research Funding; Acerta: Research Funding; Portola: Research Funding; Kite: Consultancy; AbbVie: Consultancy, Research Funding; Gilead Sciences, Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy. Dwivedy Nasta:Takeda: Research Funding; Incyte: Research Funding; Immunogen: Research Funding. Landsburg:Takeda: Research Funding; Curis: Consultancy, Research Funding. Levine:GE Healthcare: Consultancy; Tmunity Therapeutics: Equity Ownership, Research Funding; Brammer Bio: Consultancy; Novartis Pharmaceuticals Corporation: Patents & Royalties, Research Funding. Porter:Immunovative Therapies: Other: Member DSMB; Novartis: Honoraria, Patents & Royalties, Research Funding; Genentech/Roche: Employment, Other: Family member employment, stock ownship - family member; Servier: Honoraria, Other: Travel reimbursement; Incyte: Honoraria. June:Novartis: Patents & Royalties, Research Funding; Tmunity Therapeutics: Equity Ownership, Research Funding; WIRB/Copernicus Group: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celldex: Honoraria, Membership on an entity's Board of Directors or advisory committees; Immune Design: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Schuster:Genentech: Consultancy, Research Funding; Merck: Research Funding; Celgene: Consultancy, Research Funding; Nordic Nanovector: Consultancy; Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Consultancy; Gilead: Consultancy, Research Funding; Janssen: Consultancy, Honoraria.
Treatments are limited for metastatic melanoma and metastatic triple-negative breast cancer (mTNBC). This pilot phase I trial (NCT03060356) examined the safety and feasibility of intravenous ...RNA-electroporated chimeric antigen receptor (CAR) T cells targeting the cell-surface antigen cMET.
Metastatic melanoma or mTNBC subjects had at least 30% tumor expression of cMET, measurable disease and progression on prior therapy. Patients received up to six infusions (1 × 10e8 T cells/dose) of CAR T cells without lymphodepleting chemotherapy. Forty-eight percent of prescreened subjects met the cMET expression threshold. Seven (3 metastatic melanoma, 4 mTNBC) were treated.
Mean age was 50 years (35-64); median Eastern Cooperative Oncology Group 0 (0-1); median prior lines of chemotherapy/immunotherapy were 4/0 for TNBC and 1/3 for melanoma subjects. Six patients experienced grade 1 or 2 toxicity. Toxicities in at least 1 patient included anemia, fatigue, and malaise. One subject had grade 1 cytokine release syndrome. No grade 3 or higher toxicity, neurotoxicity, or treatment discontinuation occurred. Best response was stable disease in 4 and disease progression in 3 subjects. mRNA signals corresponding to CAR T cells were detected by RT-PCR in all patients' blood including in 3 subjects on day +1 (no infusion administered on this day). Five subjects underwent postinfusion biopsy with no CAR T-cell signals seen in tumor. Three subjects had paired tumor tissue; IHC showed increases in CD8 and CD3 and decreases in pS6 and Ki67.
Intravenous administration of RNA-electroporated cMET-directed CAR T cells is safe and feasible.
Data evaluating CAR T therapy in patients with solid tumors are limited. This pilot clinical trial demonstrates that intravenous cMET-directed CAR T-cell therapy is safe and feasible in patients with metastatic melanoma and metastatic breast cancer, supporting the continued evaluation of cellular therapy for patients with these malignancies.
Abstract 717
Chimeric antigen receptors (CARs) combine the antigen recognition domain of an antibody with intracellular signaling domains into a single chimeric protein. CD19 is an ideal target for ...CARs since expression is restricted to normal and malignant B cells. Inclusion of the CD137 (4-1BB) signaling domain results in potent antitumor activity and in vivo persistence of anti-CD19 CARs in mice. We reported anti-tumor activity of CAR-modified autologous T cells targeted to CD19 (CART19 cells) in 3 patients (pts) with CLL with relatively short follow up (Porter, et al NEJM 2011; Kalos et al Sci Trans Med 2011). We now report on outcomes and longer follow up from 10 pts treated with CART19 cells.
Autologous T cells collected by leukapheresis were transduced with a lentivirus encoding anti-CD19 scFv linked to 4-1BB and CD3-z signaling domains. Gene-modified T cells were expanded and activated ex-vivo by exposure to anti-CD3/CD28 beads. Pts had CLL or ALL with persistent disease after at least 2 previous treatments.
10 pts have received CART19 cells; 9 adults median age 65 yrs (range 51–78) were treated for relapsed, refractory CLL and one 7 yr old was treated for relapsed refractory ALL. CLL pts had received a median of 5 prior regimens (range 2–10) and all had active disease at the time of infusion. 3/9 CLL patients had deletion of the p53 gene. The ALL pt had chemorefractory relapse, having received chemotherapy 6 weeks prior to infusion. All CLL pts received lymphodepleting chemotherapy 4–6 days before infusions (FC, PC or bendamustine, while the ALL pt had an ALC <10 after prior chemotherapy and did not require further lymphodepletion). A median of 7.5 × 108 total cells (range 1.7–50) corresponding to 1.45 × 108 (range 0.14–5.9) genetically modified cells were infused on day 0. Median follow-up as of 8/12/2012 was 5.6 mo (range 1–24 mo). 9 pts are evaluable for response (<30d follow up in 1 pt). No pt has died. There were no infusional toxicities >grade 2. CART19 homed to the marrow in the CLL pts and marrow and CSF for the ALL patient with detectable CART19 cells in the CSF (21 lymphs/uL, 78% CAR+) day 23 after infusion. 4/9 evaluable pts achieved CR. (3 CLL, 1 ALL). 2 CLL pts had a PR lasting 3 and 5 months, and 3 pts did not respond. In the 4 pts who achieved CR, maximal expanded cells in the blood were detected at an average of 27 fold higher than the infused dose (range 21–40-fold) with maximal in-vivo expansion between day 10 and 31 post infusion. No patient with CR has relapsed. All pts who responded developed a cytokine release syndrome (CRS) manifested by fever, and variable degrees of nausea, anorexia, and transient hypotension and hypoxia. In responding CLL pts the maximal fold elevation from baseline for IFN-γ was 89–298x, IL-6 6–40x, and IL2R 5– 25x, while no significant elevation in systemic levels of TNFα or IL2 were observed. For the ALL pt, maximal elevations from baseline were: IFNγ: 6040x; IL-6: 988x; IL2R: 56x, while significant elevations in TNFα (17x) and IL2 (163x) were also observed. The timing for maximum cytokine elevation differed but in all cases correlated with peak T cell expansion in the PBMC. 5 pts with CRS required treatment; patient 03 was treated with high dose steroids with resolution of symptoms but only achieved a PR. While steroid treatment had a variable effect on the CRS, we noted that these symptoms were temporally associated with significant elevations in serum IL-6. Accordingly, 4 of these pts were treated with the IL6-receptor antagonist tocilizumab on day 3–10 with prompt resolution of fevers, hypotension and hypoxia. 3 of these patients are evaluable for response and 2 achieved a CR. For the pts in CR, CART19 expression in the blood was documented by flow cytometry at the most recent follow up for each patient: 24 mo (pt 01), 22 mo (pt 02), 3 mo (pt 100), and 2 mo (pt 09).
Autologous T cells genetically engineered to express an anti-CD19 scFv coupled to 4-1BB/CD3-z signaling domains can undergo robust in-vivo expansion, persist for at least up to 2 yrs, and can be associated with a significant CRS that responds to anti-cytokine therapy. CART19 cells can induce potent and sustained responses (6/9 responses, 4 CR) for patients with advanced, refractory and high risk CLL and relapsed refractory ALL.
Porter:Novatis: Patents & Royalties; Celgene: Honoraria; Genentech: Employment; Pfizer: Research Funding. Off Label Use: The use of CART19 cells to treat CD19+ malignancy and the use of tocilizumab to treat cytokine activation syndrome related to CART19 cells. Kalos:University of Pennsylvania: Employment, Patents & Royalties. Levine:TxCell: Consultancy, Membership on an entity’s Board of Directors or advisory committees; University of Pennsylvania: financial interest due to intellectual property and patents in the field of cell and gene therapy. Conflict of interest is managed in accordance with University of Pennsylvania policy and oversight Patents & Royalties. June:Novartis: Research Funding, entitled to receive royalties from patents licensed to Novartis, entitled to receive royalties from patents licensed to Novartis Patents & Royalties.
Patients (pts) with relapsed, and/or refractory (R/R) CLL have a poor prognosis with few effective treatment options. We have shown that infusion of autologous T cells genetically modified to express ...a chimeric antigen receptor (CAR) consisting of an external anti-CD19 domain, with the CD3ζ and 4-1BB signaling domains (CTL019 cells), can mediate potent anti-tumor effects in pts with advanced, relapsed refractory CLL. In our initial pilot study, doses of 1.7-50, x 108 mononuclear cells, corresponding to 0.14-5.9 x 108genetically modified cells, were given as a split dose infusion on days 0, 1 and 2 to 14 pts with R/R CLL and overall response rate (PR plus CR) was 57%. The majority of responses were sustained, and associated with marked expansion and long-term persistence of transduced cells. Notably, there was no obvious dose:reponse or dose:toxicity effect noted over a wide range of cell doses. To better define an optimal CTL019 cell dose, we are performing a randomized phase II study of 2 doses of CTL019 cells in pts with R/R CLL.
Pts with R/R CLL are randomly assigned to receive either 5x108 vs. 5x107transduced CTL019 cells, with the rationale that both doses induced CRs in pts on our initial pilot trial. In the initial stage, 12 evaluable pts will be treated in each arm and in stage 2, an additional 8 pts will be treated with the selected dose level. Pts have to have relapsed or persistent disease after at least 2 previous treatments and progress within 2 years of their last therapy. All pts receive lymphodepleting chemotherapy ending 3-5 days before T cell infusion. Cell infusions are given as a single dose.
As of 7/15/2013, 27 pts have been enrolled; T cells did not adequately expand in 3, 1 patient was not eligible after screening, and 10 pts have been treated including 7 men and 3 women with a median age of 63 yrs (range 59-76). 5 pts had a mutation of p53. All pts had active disease at the time of CTL019 cell infusion. Lymphodepleting chemotherapy was Fludarabine/cyclophosphamide (8), pentostatin/cyclophosphamide (1), or bendamustine (1). 4 pts have been randomized to the higher dose level (5 x 108 CTL019 cells) and 6 pts have been randomized to the lower dose level (5 x 107CTL019 cells). There were no significant infusional toxicities. Median follow-up as of July 15, 2013 was 3 mo (1.3-5) for all pts and 3.3 mo (1.3-4) for responding pts. 2 pts have achieved a CR and 2 pts achieved PR, both with clearance of CLL from the blood and marrow and >50 reduction in adenopathy, for an overall response rate of 40%. In other recipients of CTL019 cells, we have observed ongoing improvement in adenopathy over time implying there can be a continued anti-tumor response. No responding patient has progressed. Seven of 10 pts experienced a delayed cytokine release syndrome (CRS) manifested by symptoms that included high fevers, nausea, myalgias and in some cases, capillary leak, hypoxia, and hypotension, typically correlated with peak CTL019 cell expansion.
We have noted that the CRS accompanying CTL019 therapy has been associated with marked increases of serum IL6 and can be rapidly reversed with the IL6-receptor antagonist tocilizumab. The CRS required intervention in 2 pts, one who responded and one who did not respond to CTL019. Treatment was initiated for hemodynamic or respiratory instability and was effective in reversing signs and symptoms of CRS in both pts.
A preliminary analysis through July 15, 2013 does not yet suggest a dose:response or dose:toxicity relationship. 2 of 4 recipients of the higher dose CTL019 responded, and 2 of 6 recipients at the lower dose level responded. The 7 pts who experienced a CRS included all 4 responding pts and 3 pts who did not respond. The CRS occurred in 3/4 recipients of higher dose CTL019 cells and 4/6 of recipients of lower dose CTL019 cells. CTL019 expansion in-vivo and persistence over the follow up period was noted in all responding pts.
In this ongoing dose optimization study of CTL019 cells, 4 of the first 10 pts treated have responded within 3 months. With short follow-up, as yet there is no suggestion that there is a dose:response or dose:toxicity relationship at the dose ranges being studied. These cells can undergo robust in-vivo expansion and from other studies (ASH 2013) can persist for at least 3 yrs. This trial confirms that CTL019 cells can induce potent responses for pts with advanced, relapsed and refractory CLL.
Porter:Novatis: IP and potential royalties with COI managed according to policies of the University of Pennsylvania, IP and potential royalties with COI managed according to policies of the University of Pennsylvania Patents & Royalties, Research Funding; Genentech: Spouse employment, Spouse employment Other. Off Label Use: CTL019 cells to treat CLL. Kalos:Novartis corporation: CART19 technology, CART19 technology Patents & Royalties; Adaptive biotechnologies: Member scientific advisory board , Member scientific advisory board Other. Grupp:Novartis: Research Funding. Chew:Novartis: Patents & Royalties. Shen:Novartis Pharmaceuticals: Employment, Equity Ownership. Wood:Novartis Pharmaceuticals: Employment, Equity Ownership. Litchman:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Zheng:Novartis: Patents & Royalties. Levine:Novartis: cell and gene therapy IP, cell and gene therapy IP Patents & Royalties. June:Novartis: Patents & Royalties, Research Funding.
Chimeric antigen receptors (CARs) combine the antigen recognition domain of an antibody with intracellular signaling domains into a single chimeric protein. CD19 is an ideal target for CARs since ...expression is restricted to normal and malignant B cells. Inclusion of the CD137 (4-1BB) signaling domain results in potent antitumor activity and in-vivo persistence of anti-CD19 CAR-modified T cells in mice. Lentiviral transduction into T cells facilitates strong surface expression of the CAR. We reported anti-tumor activity of CAR-modified autologous T cells targeted to CD19 (CTL019 cells) in 3 patients (pts) with CLL with relatively short follow up (Porter, et al NEJM 2011; Kalos et al Sci Trans Med 2011). We now report on outcomes and longer follow up from our pilot study treating 14 pts with relapsed, refractory CLL.
Autologous T cells collected by leukapheresis were transduced with a lentivirus encoding anti-CD19 scFv linked to 4-1BB and CD3-ζ signaling domains. Gene-modified T cells were expanded and activated ex-vivo by exposure to anti-CD3/CD28 beads. Pts had to have relapsed or persistent disease after at least 2 previous treatments (1 prior therapy for patients with p53 mutation) and progressed at least within 2 years of their last therapy. All pts received lymphodepleting chemotherapy ending 3-5 days before T cell infusion. The target dose of cells was 5 x 109 mononuclear cells with an expected transfection efficiency of 10-40% (total CTL019 dose 5x108 – 2 x 109 total cells). Cell infusions were planned over 3 days (10% on day 1, 30% of day 2, and 60% on day 3) but were held for fevers or other toxicity.
14 patients were treated on this pilot study including 12 men and 2 women with a median age of 67 (51-78). Pts had received a median of 4 prior therapies (1-10) and 6 pts had a mutation of p53. All pts had active disease at the time of CTL019 cell infusion. Lymphodepleting chemotherapy was Fludarabine/cyclophosphamide (3), pentostatin/cyclophosphamide (5), or bendamustine (6). A median of 7.5 x 108 total cells (range 1.7-50), corresponding to 1.4 x 108(range 0.14-5.9) genetically modified cells were infused over day 0, 1 and 2.
There were no infusional toxicities >grade 2 though 6 pts developed fevers within 24 hrs of infusion #1 (3) or #2 (3) and did not receive additional CTL019 cells. Median follow-up as of July 15, 2013 was 9.4 mo (4-35) for all pts and 16 mo (5-35) for the 8 responding pts. 3 patients (21%) achieved a CR (follow-up 11, 34, and 35 mo), 5 (36%) achieved a PR (med follow up 11 mo, range 5-27 mo) and 6 (43%) had no response, for an overall major response rate of 57%. 2 of 5 pts with a PR progressed 4 mo after infusion with CD19+ CLL, and no patient with a CR has relapsed.
Comparing responders to non-responders, there has been no association between response and patient age (66 vs 67 yrs), number of prior therapies (median 4 each), cell dose (7.5 vs 11.5 x 108MNC), or p53 mutation (3/8 vs 3/6, p>0.9), implying that within the dose ranges studied, there is no obvious dose:response relationship.
All responding pts developed a delayed cytokine release syndrome (CRS), concurrent with peak T cell expansion, and was manifested by fever, and variable degrees of nausea, anorexia, myalgias, and transient hypotension and hypoxia. Detailed cytokine analysis showed marked increases from baseline values of IL6, IFN-γ, and IL2R, while no significant elevation in systemic levels of TNFα or IL2 were observed. The CRS required intervention in 5 patients. Treatment was initiated for hemodynamic or respiratory instability and was rapidly reversed in all cases with corticosteroids in 1 pt and the IL6-receptor antagonist tocilizumab (4 pts); 3 of these 4 pts also received 1 or 2 doses of corticosteroids. Persistence of CTL019 cells has been detected by flow cytometry in all 6 pts with ongoing responses 5-35 months after infusion, and all patients have sustained B cell aplasia without any unusual infectious complications.
CTL019 cells are autologous T cells genetically engineered to express an anti-CD19 scFv coupled to 4-1BB/CD3-ζ signaling domains. These cells can undergo robust in-vivo expansion and can persist for at least 3 yrs. CTL019 therapy is associated with a significant CRS that responds rapidly to anti-cytokine treatment. CTL019 cells can induce potent and sustained responses (8/14) for patients with advanced, relapsed and refractory CLL regardless of p53 mutation status.
Porter:Novartis: Patents & Royalties, Research Funding; Genentech: Spouse employment, Spouse employment Other. Off Label Use: CTL019 cells to treat CLL. Kalos:Adaptive biotechnologies: Member scientific advisory board , Member scientific advisory board Other; Novartis corporation: CART19 technology, CART19 technology Patents & Royalties. Grupp:Novatis: Research Funding. Lledo:Novartis: Research Funding. Chew:Novartis: Patents & Royalties. Zheng:Novartis: Patents & Royalties. Levine:Novartis: cell and gene therapy IP, cell and gene therapy IP Patents & Royalties. June:Novartis: Patents & Royalties, Research Funding.
We have shown that infusion of autologous T cells genetically modified to express a chimeric antigen receptor (CAR) consisting of an external anti-CD19 domain, with the CD3z and 4-1BB signaling ...domains (CTL019 cells), can mediate potent anti-tumor effects in patients (pts) with advanced, R/R CLL and other CD19+ malignancies. In our initial pilot study, doses of 0.14-5.9 x 108 CTL019 cells were given to 14 pts with R/R CLL and the overall response rate (PR plus CR) was 57%. The majority of responses were sustained, and associated with marked expansion and long-term persistence of transduced cells. Given that CARTs can be self-replicating, it is unknown if there is an optimal biologic dose or merely a necessary threshold dose that must be achieved. To better define an optimal dose, we are performing a randomized phase II study of 2 doses of CTL019 cells in pts with R/R CLL.
Eligible pts have relapsed or persistent CLL after at least 2 previous treatments and progressed within 2 years of their last therapy. Pts are randomized to receive either 5x108 or 5x107 CTL019 cells. All pts receive lymphodepleting chemotherapy ending 3-5 days before T cell infusion. In stage 1, 12 evaluable pts per arm will be treated and in stage 2, an additional 8 pts will be treated at the selected dose. Data is examined through 7/1/14.
RESULTS
To date, 30 pts have been randomized; T cells did not adequately expand in 1, 1 pt was not eligible after screening and 26 pts were treated. 13 pts have been randomized to the higher dose (5 x 108 CTL019 cells) and 13 pts have been randomized to the lower dose (5 x 107 CTL019 cells). Pts were 67% men with a median age of 62 yrs (range 54-76). 10 pts had a known mutation of p53 or 17p del, and 2 pts had failed prior ibrutinib. Pts had received a median of 3 prior therapies (range 2-10) and all had active disease at the time of CTL019 infusion. 3 pts who did not receive the targeted dose are evaluable for toxicity but not response, leaving 23 are evaluable for response.
Median follow-up for all 26 pts was 7.3 mo (range 1-16 mo). Of 23 evaluable pts, 5 (22%) achieved a CR and 4 (17%) achieved PR, for an overall response rate of 35% (95% exact CI 20-61%). 3 responding pts progressed; 1 pt in CR and 1 in PR progressed at 1 and 6 mo after infusion with aggressive CD19-negative transformed lymphoma, and one pt who achieved PR progressed 9 mo after infusion with CD19+ CLL having lost persisting CTL019 cells.
14 of 26 pts experienced a delayed CRS. We devised a novel CRS grading scale that will be presented. Detailed cytokine profiles show marked elevations in IL6 and other cytokines during CRS CRS required intervention in 3 pts with tocilizumab (with or without steroids and additional anti-cytokine therapy) for hemodynamic or respiratory instability and was effective in reversing symptoms of CRS in all pts. 2 of these 3 responded to CTL019. There was no treatment-related mortality.
response or dose:toxicity relationship. 6 of 11 evaluable pts on the high dose responded, and 3 of 12 recipients at the lower dose responded (p=0.21). 6 of 11 evaluable on the high dose and 7/12 recipients of the low dose experienced CRS (p=1.0). The 13 evaluable pts who experienced CRS included 6 of 9 responding pts and 7 of 14 non- responders (p=0.67), and one pt not evaluable for response. All statistical tests were based on Fisher’s exact test.
CTL019 expansion in-vivo was noted in all responding pts. By flow cytometry, at peak expansion CTL019 cells represented 0.1-84.6% of CD3+ cells in the 9 responding pts (median 14.7%) and 0-10.6% (median 0.35%) in the 14 non-responders.
Neither response nor expansion correlated with typical patient or disease characteristics including age, number of prior therapies or mutated P53. Data regarding T cell phenotype before and after CAR modification will be presented.
In this ongoing dose optimization study of CTL019 cells, 9 of the first 23 evaluable pts have responded. As yet, there is no suggestion of a dose:response or dose:toxicity relationship at the doses being studied. CTL019 cells from R/R CLL pts can undergo robust in-vivo expansion and are associated with a CRS, manageable with anti-cytokine directed therapy. A novel grading scale was developed to better capture the clinical severity of CRS and help guide timing of intervention. This ongoing trial confirms that CTL019 cells can induce potent and durable responses for pts with advanced, R/R CLL with manageable toxicity.
Porter:Novartis: Patents & Royalties, Research Funding; Genentech (spouse employment): Employment. Off Label Use: Use of genetically modified T cells (CTL019) to treat CLL and use of tocilizumab to treat cytokine release syndrome.. Frey:Novartis: Research Funding. Hwang:NVS: Research Funding. Lacey:Novartis: Research Funding. Chew:Novartis: Patents & Royalties, Research Funding. Grupp:Novartis: Research Funding. Kalos:Novartis: Patents & Royalties, Research Funding. Litchman:Novartis: Employment. Mahnke:Novartis: Research Funding. Shen:Novartis: Employment. Wood:Novartis Pharma: Employment. Zheng:Novartis: Patents & Royalties, Research Funding. Levine:Novartis: Patents & Royalties, Research Funding. June:Novartis: Research Funding, Royalty income Patents & Royalties.
PDF
