LIGAND-INDUCIBLE, PROSTATE STEM CELL CELLS IN ADVANCED ...€¦ · esmo.org ligand-inducible, prostate stem cell antigen (psca) -directed gocar-t® cells in advanced solid tumors:

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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




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


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


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 = 7,686 copies

PSCA = 8,243 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




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 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

Documents

LIGAND-INDUCIBLE, PROSTATE STEM CELL CELLS IN ADVANCED ...€¦ · esmo.org ligand-inducible, prostate stem cell antigen (psca) -directed gocar-t® cells in advanced solid tumors: