Immunotherapy for Lymphomas

CK Das

AIIMS, New Delhi

300 patientsDLBCL

200 Cured with RCHOP

100 RelapseOr refractory

50 Transplantcandidate

50 Transplantineligible

25 Chemo-refractory

25 Respond and ASCT

Friedberg 2011 ASH Educational Session

210 Cured

90 receive Palliation. Most likely die from DLBCL

15 patients relapse

10 Cured after ASCT

The Unmet need

Immunotherapy Immunotherapy

AntibodyCytokineAdaptive

cell Therapy

Anti Idiotype Vaccine

Immuno Check point

Inhibitor

IIPembrolizumab

Nivolumab Ipilimumab

UrelumabDurvalumab

IIIId

Vaccine in FL

IICD19 CART

therapy

CD30 CART

therapy

IIIL-12 in CTCL

refractory DLBCL

IIAnti-CD19

Ab

Anti-CD37 ab

Anti CD22 radioantib

ody

HL: Most immunogenic malignancy

9p amplification

EBV: PD-L1 overexpression

Nivolumab in HL

Ansell SM et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J Med 2015;372(4):311-9 UPDATED RESULT ASH 2015

23 relapsed or refractory Hodgkin's lymphoma

78% post transplant relapse

78% post brentuximab vedotin

nivolumab (3 mg per kg) every 2 weeks

any grade and of grade 3 occurred in 78% and 22% of

Response Patients (N = 23)

Objective response rate 87% Complete response 22% Partial response 65%Stable disease 13%Median duration of response Not reached*Median PFS Not reached*1-year OS 91%

median follow-up of 101 weeks

Nivolumab FDA Approval:CheckMate-205 & CheckMate-039

The median age was 37 years (range, 18-72)

The median number of prior systemic regimens received was 5 (range, 3-15).

98 %Auto HSCT,74 % Adcetris

three mg/kg IV over 60 minutes every two weeks until disease progression or unacceptable toxicity.

The median duration of therapy was 8.3 months (range, 1.9-24

The ORR of 65 percent (7%CR).

The median duration of response was 8.7 months

The median time to response was 2.1 months

AE fatigue (32 %), upper respiratory tract infection (28%) ,pyrexia (24 %), diarrhea (23 %) and cough (22%)

Nivolumab trial nivolumab :Hodgkin lymphoma, human T cell

leukemia virus (HTLV)-associated leukemia/lymphoma nivolumab combined with brentuximab vedotin

Hodgkin lymphoma,non-Hodgkin lymphoma. • A phase I/II study of nivolumab combined with

urelumab (anti-4-1BB/CD137 antibody) B cell non-Hodgkin lymphoma

nivolumab combined with ipilimumab lymphoma who are at high risk for recurrence

nivolumab combined with ibrutinib, nivolumab +/- ipilimumab or lirilumab, an anti-KIR

antibody in lymphoma

Pembrolizumab in HL: Keynote 13 cHL cohort

Response ASCT failure(n = 23)

ASCT ineligible/refused(n = 9)

All patients(N = 31)

Overall response 73% 44% 65% Complete remission 14% 22% 16% Partial remission 59% 22% 48%

Stable disease 18% 33% 23%Progressive disease 9% 22% 13%PFS at 24 weeks – – 69%

Armand P, Shipp MA, Ribrag V et al. PD-1 blockade with pembrolizumab in patients with classical Hodgkin lymphoma after brentuximab vedotin failure: Safety, efficacy, and biomarker assessment. Presented at the 57th American Society of Hematology (ASH) Annual Meeting. December 5-8, 2015; Orlando, FL. Abstract 584

31 patients (median age, 32 years)

100% failed prior brentuximab.

71% failed prior ASCT, 29% ineligible or refused ASCT.

pembrolizumab 10 mg/kg every 2 weeks for up to 2 years

most common AEs diarrhea (16%) and nausea (13%)

Current Trials :Pembrolizumab

pembrolizumab in relapsed or refractory B cell non-Hodgkin lymphoma ,follicular lymphoma

pembrolizumab after autologous stem cell transplantation in patients with relapsed or refractory Hodgkin lymphoma and diffuse large B cell lymphoma

pembrolizumab :relapsed or refractory T cell non-Hodgkin lymphoma

pembrolizumab :advanced primary mediastinal large B cell lymphoma (NCT02576990).

pembrolizumab : recurrent PCNSL

Durvalumab (PDL1Ab) +/- Tremelimumab: (CTLA-4 Ab)

Durvalumab + tremelimumab CTCL,DLBCL, pediatric lymphoma

Durvalumab +ibrutinib :relapsed or refractory lymphoma

Checkpoint blockade after SCT

Pidilizumab R/R DLBCL after ASCT:72 patients post-ASCT pidilizumab. # 3 Cycle response rate :51% ( 34% CR rate) The 18-month PFS: 72% Poor risk (PET+)18-month PFS was 70%

vs Historically controle 52%

Armand etal J Clin Oncol 2013;31(33):4199-4206.

Anti Idiotype Vaccine• Idiotype of the Ig antigen

of a B-cell lymphoma can be used as a tumor-specific immunogen

• Keyhole lympet hemocyanin (KLH) carrier serves as an immune stimulant

• GM-CSF administered concurrently at site of injection as an adjuvant

Anti Idiotype Vaccine Process

CD4+

• Addition of GM-CSF Adjuvant improves vaccine potency

CD8+cytokines

Lymphoma cell

Y

(Kwak et al. PNAS 1996)

Phase I/II Clinical Trial (Nature Med 1999):

• Vaccine induces molecular remissions

•

Tumor protein

Phase III Controlled Clinical Trial(J Clin Oncol 2011)

• Vaccine prolongs DFS in patients in a chemotherapy- induced remission (n=117, p=0.045)

PreclinicalIsolate antigen

Package in Delivery system

Id vaccine in Follicular Lymphoma

LNBx

Assign CR

Stratify for IPI1, cycles of Chemotherapy2

2:1 RandomizationChemo

• Primary endpoint: disease-free survival• 14 sites enrolled patients from 2000-2007

6 - 12 months 6 months6 - 8 months

(Id Vaccine)

(Control)

Disease Free Survival from Randomization

log-rank p=0.045

Median Follow-up 56.6 mo (range 12.6 –

89.3)

Median DFSId vaccine = 44.2 moControl vaccine = 30.6

mo

HR = 0.62; [95% CI: 0.39,0.99] (p=0.047)

Control vaccine (n=41)

Id vaccine( n=76)

Schuster , Neelapu et al. (Kwak) J Clin Oncol 29:2787, 2011

On going Studies Imprime PGG refractory non-Hodgkin

lymphoma CDX-301 (Flt3L plus Poly-ICLC (a Toll-like

receptor agonist B cell lymphoma Toll-like receptor 9 agonist: low grade

lymphomas (NCT02266147) immunotransplantation in MCL

MCL cells are activated with TLR vaccine for patients in remission Transplant +Stimulated T cell

100

10

1

0.1

0.01

T cell expansion

ex vivoCancerVaccine

“Thresholdfor cure”% Tumor

specificT cells in

vivo

Hypothesis

Concepts of Adaptive Immunotherapy

Adoptive Transfer of T Cells as Therapy for Cancer

CAR T Cell Therapy

Month +3 response assessment

CAR-T Cells for Rel/Ref CD19 Positive NHLs: Treatment Schema

CD19+ Lymphoma• Eligibility

determination• Enrollment

Apheresis• Baseline immune assays

Restaging and Lymphodepleting ChemotherapyCT Scans and Bone Marrow. Therapy Physician Choice.

Ends 1-4 Days before CTL019 infusion

CTL019 Infusion, Monitoring and Response Assessments

Day 0

Month +1

Month +2 and +3evaluations

Quarterly f/u x 2 yr F/U 15 years

Adverse event monitoring

CTL019 infusion

= Clinical evaluation; immune/CTL019 assays

Day -1

Schuster et al. ASCO 2015, Abst 8516.

DLBCL: ORR at 3 Mo 50% (N = 13) Best Response 50% (N = 13)

- CR: 2- PR: 4- PD: 6- Response not yet assessed:

1

- CR: 5- PR: 1- PD: 6- Response not yet assessed: 1• 3 PR at 3 mo converted to CR at 6; 1 PR at 3 mo had PD at 6

CAR-T Cells for CD19 Positive NHLs: Response Rates for DLBCL and FL

FL: ORR at 3 Mo 100% (N = 7) Best Response 100% (N = 7)

- CR: 3- PR: 4

- CR: 6- PR: 1

• 3 PR at 3 mo converted to CR by 6 mo; 1 PR at 9 mo had PD at 12

Schuster et al. ASCO 2015, Abst 8516.

On-going Studies CD19 CAR T cell : refractory DLBCL,

refractory PMBL, and transformed FL CD30 CAR T cell :CD30+ relapsed or

refractory Hodgkin and non-Hodgkin lymphoma

Conclusions

Immunotherapy addresses the unmet needs

The breakthrough for Lymphoma treatment : Nivolumab& Pembrolizumab