LIGAND-INDUCIBLE, PROSTATE STEM CELL CELLS IN ADVANCED ...€¦ · esmo.org ligand-inducible,...
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LIGAND-INDUCIBLE, PROSTATE STEM CELL ANTIGEN (PSCA)-DIRECTED GoCAR-T® CELLS IN ADVANCED SOLID TUMORS: PRELIMINARY RESULTS FROM A DOSE ESCALATION STUDYCarlos R. Becerra,1 Pamela Hoof,1 Scott Paulson,1 Gulam A. Manji,2Olivia Gardner,3 Aditya Malankar,3 Joanne Shaw,3 Devin Blass,3Brandon Ballard,3 Xiaohui Yi,3 Madhavi Anumula,3 Aaron Foster,3Joseph Senesac,3 Paul Woodard3
1Baylor University Medical Center, Dallas, TX, USA; 2Columbia University Medical Center/New York Presbyterian Hospital, New York, New York, USA; 3Bellicum Pharmaceuticals, Houston, TX, USA.
DISCLOSURE SLIDEDr. Becerra has received honoraria from Taiho Pharmaceutical; has consulted for Agenus, Bayer, Heron, Ipsen, SOBI, and Takeda; and has participated in speakers’ bureaus for Bristol-Myers Squibb, Celgene, Merck Serono, and Taiho Pharmaceutical
This study was sponsored by Bellicum Pharmaceuticals
INDUCIBLE MYD88/CD40
TLRs 7,8, 9
TLRs 1,2, 4–6
MyD88TIR
AP1 NFκB IRF7
CD40
Cytoplasmic domain
NFκB AP1
MyD88
NFκB AP1IRF7
Rimiducid
FKBP12v36
FKBP12v36
CD40
MyD88
MyD88 CD40 iMC
Proinflammatory cytokines, Type I IFNs, T Cell Proliferation and PersistenceOther immune functions
IFN, interferon; iMC, inducible MyD88/CD40; TIR, toll/interleukin-1 receptor; TLR, toll-like receptor.
(iMC)
GoCAR-T®: BPX-601 OVERVIEW
CAR, chimeric antigen receptor; iMC, inducible MyD88/CD40; PSCA, prostate stem cell antigen; Rim, rimiducid; TCR, T cell receptor.
• Autologous T cell product candidate
• Antigen-specific activation through PSCA-CD3ζ CAR
• Rimiducid-dependent costimulationthrough inducible MyD88/CD40 domain
Hypothesis: GoCAR-T design optimizes BPX-601 for antigen-directed and -independent T cell activation, proliferation, and persistence, which may afford BPX-601 enhanced
clinical activity relative to traditional CAR-T cell therapies for solid tumors
Controllable Functions
ANTIGEN-INDEPENDENT
SURVIVAL
Cell Autonomous
FunctionsANTIGEN-
DEPENDENT CYTOTOXICITY
• Small, GPI-anchored cell-surface protein of the Thy-1/Ly-6 family2
• Expressed in 60–80% of pancreatic ductal adenocarcinomas3,4
• Also expressed in prostate, bladder, gastric, and other solid tumors and correlates with disease stage5
• Low basal expression on normal prostate epithelium, urinary bladder, kidney, esophagus, stomach, and placenta1
• Low toxicity profile with PSCA-targeted antibodies in prostate and pancreatic cancer6,7
PROSTATE STEM CELL ANTIGEN (PSCA) TARGET RATIONALE
GPI, glycosylphosphatidylinositol; hACTB, human beta-actin; LoQ, limit of quantification.1. Bellicum data on file; 2. Saeki N, et al. Clin Cancer Res. 2010;16:3533–3538; 3. Argani P, et al. Cancer Res. 2001;61:4320–4324; 4. Wente MN, et al. Pancreas. 2005;31:119–125; 5. Abate-Daga D, et al. Hum Gene Ther. 2014;25:1003–1012; 6. Morris MJ, et al. Ann Oncol. 2012;23:2714–2719; 7. Wolpin BM, et al. Ann Oncol. 2013;24:1792–1801.
PSCA screening of pancreatic tumors1
Cutoff for PSCA+
BP-012 PHASE 1/2 STUDY DESIGN
• Part 1 objectives: safety, tolerability, MTD and/or RDE for use in Part 2
• Part 1 status: enrollment ongoing in Cohort 5
PSCA+, advanced pancreatic
cancer
Apheresis
Lymphodepletion (cyclophosphamide)
Between Days −42
and −8
Day −3 Day 0 Day 7
Routine safety and efficacy evaluations up to 60 months
Part 2 (Phase 2): multi-arm dose
expansion in PSCA+ pancreatic, gastric, and prostate cancer
Part 1 (Phase 1)
MTD, maximum tolerated dose; PSCA, prostate stem cell antigen; RDE, recommended dose expansion.
Cohort 0:1.25 x 106 cells/kg
Cohort 3:1.25 x 106 cells/kg
Cohort 4:2.5 x 106 cells/kg
Cohort 5:5.0 x 106 cells/kg
Single infusion BPX-601 cell dose escalation (3+3) based on safety
Cohorts 3, 4, 5:
Single-dose rimiducid0.4 mg/kg
NCT02744287
PATIENT DEMOGRAPHICS AND CLINICAL CHARACTERISTICS
* Cytoxan 1 g/m2 by IV infusion on Day −3; † PSCA (copies per 106 copies hACTB) was measured at screening.CTX, cyclophosphamide; hACTB, human beta-actin; LD, lymphodepletion; PSCA, prostate stem cell antigen; Rim, rimiducid.
Cohort Patient Age Sex Tumor TypeBPX-601 Dose(106 cells/kg)
Rim (Y/N) LD Regimen*
# Prior Systemic Therapies PSCA (copies)†
0
0A 50 F Pancreas 1.25 N CTX only 1 5,000
0B 58 F Pancreas 1.25 N CTX only 3 377,000
0C 65 F Pancreas 1.25 N CTX only 5 15,000
3
3A 59 F Pancreas 1.25 Y CTX only 2 34,000
3B 70 M Pancreas 1.25 Y CTX only 1 7,000
3C 58 F Pancreas 1.25 Y CTX only 1 31,000
4
4A 71 F Pancreas 2.5 Y CTX only 2 7,686
4B 65 M Pancreas 2.5 Y CTX only 4 8,243
4C 60 F Pancreas 2.5 Y CTX only 2 354,730
5
5A 61 M Pancreas 5.0 Y CTX only 3 14,238
5B 64 M Pancreas 5.0 Y CTX only 1 19,533
5C 59 M Pancreas 5.0 Y CTX only 5 969,094
SAFETY SUMMARYMost common AEs reported by > 1 patient Total (N=12)
Any Event, n (%) 12 (100)
Fatigue 4 (33)
Abdominal pain upper 3 (25)
Hypotension 3 (25)
Abdominal pain 2 (17)
Back pain 2 (17)
Diarrhea 2 (17)
Flatulence 2 (17)
Nausea 2 (17)
Pyrexia 2 (17)
• No DLTs, neurotoxicity, or events of cytokine release syndrome were observed• Pyrexia is the only treatment-related AE reported by >1 patient (n=2)
• Grade 1–2 on Day 0 following BPX-601 infusion• Both events resolved within 24–36 hours with supportive care
AE, adverse event; DLT, dose-limiting toxicity.
BPX-601 T CELL EXPANSION AND PERSISTENCE
* Vector copy number < limit of quantification.CTX, cyclophosphamide; LD, lymphodepletion; PSCA, prostate stem cell antigen; Rim, rimiducid.
-70
2 0 0 0
4 0 0 0
6 0 0 0
8 0 0 0
1 0 0 0 0
0 5 1 0 1 5 2 0 2 5 3 0 3 5 4 0 4 5
*
-70
2 0 0 04 0 0 06 0 0 08 0 0 0
1 0 0 0 0
0 5 1 0 1 5 2 0 2 5 3 0 3 5 4 0 4 5
2 0 0 0 02 5 0 0 0
* * * *
-70
2 0 0 0
4 0 0 0
6 0 0 0
8 0 0 0
1 0 0 0 0
0 5 1 0 1 5 2 0 2 5 3 0 3 5 4 0 4 5
* * *
-70
2 0 0 0
4 0 0 0
6 0 0 0
8 0 0 0
1 0 0 0 0
0 5 1 0 1 5 2 0 2 5 3 0 3 5 4 0 4 5
-70
2 0 0 0
4 0 0 0
6 0 0 0
8 0 0 0
1 0 0 0 0
0 5 1 0 1 5 2 0 2 5 3 0 3 5 4 0 4 5
* * * *
-70
2 0 0 04 0 0 06 0 0 08 0 0 0
1 0 0 0 0
0 5 1 0 1 5 2 0 2 5 3 0 3 5 4 0 4 5
2 0 0 0 02 5 0 0 0
* * *
-70
2 0 0 0
4 0 0 0
6 0 0 0
8 0 0 0
1 0 0 0 0
0 5 1 0 1 5 2 0 2 5 3 0 3 5 4 0 4 5
* * * *
-70
2 0 0 0
4 0 0 0
6 0 0 0
8 0 0 0
1 0 0 0 0
0 5 1 0 1 5 2 0 2 5 3 0 3 5 4 0 4 5T im e (D a y s )
-70
2 0 0 0
4 0 0 0
6 0 0 0
8 0 0 0
1 0 0 0 0
0 5 1 0 1 5 2 0 2 5 3 0 3 5 4 0 4 5
* *
-70
2 0 0 04 0 0 06 0 0 08 0 0 0
1 0 0 0 0
0 5 1 0 1 5 2 0 2 5 3 0 3 5 4 0 4 5
2 0 0 0 02 5 0 0 0
-70
2 0 0 0
4 0 0 0
6 0 0 0
8 0 0 0
1 0 0 0 0
0 5 1 0 1 5 2 0 2 5 3 0 3 5 4 0 4 5
Cohort 42.5x106/kg + Rim
PSCA = 34,000 copies
PSCA = 7,000 copies
PSCA = 31,000 copies
PSCA = 7,686 copies
PSCA = 8,243 copies
PSCA = 354,730 copies
PSCA = 14,238 copies
PSCA = 19,533 copies
Cohort 01.25x106/kg
Cop
ies/
µg g
DN
A
Cohort 55x106/kg + Rim
CAR-T CAR-T CAR-T CAR-TRim Rim Rim
PSCA = 5,000 copies
PSCA = 377,000 copies
PSCA = 15,000 copies
Cohort 31.25x106/kg + Rim
Time (Days)
• Limited evidence of LD with CTX-only regimen (79% ± 25% of cells remained)
• Rapid cell expansion by Day 4, but no persistence without Rim
• With single-dose Rim:
Cell expansion of 3- to 20-fold within 7 days in 4 patients
Cell persistence of >3 weeks in 3 patients
PERIPHERAL CYTOKINE PROFILES OVER TIME
The orange, black, and blue lines represent data for an individual patient in the indicated cohort for multiple cytokines. Rim, rimiducid.
01 0 0 02 0 0 03 0 0 04 0 0 05 0 0 0
0
4 0
8 0
1 2 0
-1 0 0 1 0 2 0 3 0 4 0 5 0D a y p o s t-T c e ll in fu s io n
-1 0 0 1 0 2 0 3 0 4 0 5 0D a y p o s t-T c e ll in fu s io n
-1 0 0 1 0 2 0 3 0 4 0 5 00
5 01 0 01 5 02 0 02 5 0
D a y p o s t-T c e ll in fu s io n-1 0 0 1 0 2 0 3 0 4 0 5 0
D a y p o s t-T c e ll in fu s io n
Seru
m c
ytok
ines
(pg/
mL) IP-10
TNF-α
IL-6
CAR-TRim
CAR-T CAR-T CAR-TRim Rim
IP-10 IP-10 IP-10
TNF-α TNF-α TNF-α
IL-6IL-6 IL-6
Cohort 31.25x106/kg + Rim
Cohort 42.5x106/kg + Rim
Cohort 01.25x106/kg
Cohort 55x106/kg + Rim
Days post-BPX-601 infusion
EVIDENCE OF ANTI-TUMOR ACTIVITY IN BPX-601–TREATED PATIENTS
CA19-9, cancer antigen 19-9; CR, complete response; PD, progressive disease; PR, partial response; PSCA, prostate stem cell antigen; SD, stable disease.
CohortBest Response (RECIST)
CR PR SD PD
0 0 0 1 2
3 0 0 2 1
4 0 0 2 1
Two patients with SD had tumor shrinkage >20%
Patient 3A: 2 prior therapies; PSCA = 34,000 copiesBaseline Month 1
• Lesion longest diameter: 70 mm• CA19-9: 294
• Lesion longest diameter: 57 mm• CA19-9: 152.6• Overall response: SD (−15%)
• Lesion longest diameter: 49 mm• CA19-9: 207.2• Possible new lesion• Overall response: SD (−25%)
Month 4
• Lesion longest diameter: 40 mm• CA19-9: 641.4• New lesion confirmed• Overall response: PD
Month 2
EVIDENCE OF ANTI-TUMOR ACTIVITY IN BPX-601–TREATED PATIENTS
PSCA, prostate stem cell antigen.
Baseline• At Month 4, no
clinical symptoms of worsening disease
• Ongoing treatment-free interval >19 weeks
Month 1
• Slightly enlarged lesion with ring enhancement characteristic of pseudoprogression
Month 2
• Similar lesion size• Increased density• Continued ring enhancement
Patient 4B: 4 prior therapies; PSCA = 8,243 copies
SWIM PLOT AFTER BPX-601 ADMINISTRATION
PD, progressive disease; pseudo PD, pseudoprogression, progressive disease; SD, stable disease.
Disease control without new therapy was 16 and >18 weeks (ongoing) in 1 and 3 patients, respectively
Next treatment not started
SDPD
Death
Pseudo PD (clinical exam)
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 31Weeks
3A (2)3B (1)
3C (1)
4A (2)
4B (4)
4C (2)
Patie
nts
(# o
f prio
r sys
tem
ic th
erap
ies)
5A (3)
5B (1)
5C (5)
• Administration of BPX-601 with single-dose rimiducid was well tolerated
No observed cytokine release syndrome or neurotoxicity of any grade
Most frequent AEs were consistent with those experienced by advanced cancer patients undergoing cytotoxic chemotherapy or other cancer immunotherapies
Treatment-related AEs were limited, mild to moderate in intensity, and resolved with supportive care
• Despite inadequate lymphodepletion with cyclophosphamide alone, BPX-601 displayed enhanced expansion and prolonged persistence in some patients treated with rimiducid
• Evidence of biological activity/stable disease have been observed in this heavily pre-treated patient population
• Part 2 (opening soon) will include more intense lymphodepletion with cyclophosphamide/fludarabine, a repeat-dose rimiducid infusion schedule, and gastric and prostate cancer patients
SUMMARY AND CONCLUSIONS