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Annual Oncology Symposium 5/20/2016

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Immunotherapy Approaches in Lymphoma

John Kuruvilla MD FRCPC


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Research SupportLeukemia and Lymphoma Society US, Rasch FoundationRoche,

Employee N/A

Consultant Abbvie, BMS, Gilead, Janssen, Roche

Major Stockholder N/A

Speakers Bureau N/A

Honoraria Abbvie Amgen, BMS, Celgene, Gilead, Roche, Janssen, Lundbeck, Merck Seattle Genetics,

Scientific Advisory Board Lymphoma Canada (Chair)

I will likely discuss all sorts of off-label use of agents as well as investigational agents

Disclosures for John Kuruvilla MD


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The “old era” of immunotherapy

• A few examples in lymphoma of immunotherapy– Allogeneic stem cell transplantation– Interferon-a– Anti-idiotype vaccination


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Objectives – Immunotherapy Approaches in Lymphoma

• Assess the new era of immunotherapies• Review checkpoint inhibitors and adoptive

immunotherapies• Recognize how immunotherapies should be used

in lymphoma therapy.

• Create some controversy…


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First example of GVLY – Johns Hopkins Comparison of ASCT and ALLO

• N=118• ASCT 80 (purged)• ALLO 38• Pre-SCT status

predicts outcome• No OS difference• Reduced REL

suggestive of anti-tumour effect

ASCT

ALLO

Jones Blood 1991


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DLI and wIST in NHL

From Porter et al BBMT 2010


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IFN-2 in FL – Meta-Analysis Shows Benefit

• Meta-analysis performed of 10 randomized trials in newly diagnosed FL (1922 patients) – trial heterogeneity re:– Timing and dose of IFN– Type of chemotherapy given (anthracycline or not)

• Survival advantage demonstrated when:– In conjunction with relatively intensive chemo– Dose 5 million units– Cumulative dose 36 million units per month– IFN given with chemotherapy as opposed to as maintenance

Rohatiner et al. JCO Vol. 23 No. 10, 2005


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OS Advantage with maintenance IFN

Rohatiner et al. JCO Vol. 23 No. 10, 2005


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PFS Advantage with Immune Response (not vaccine) in FL

• Immune response assessed by development of humoral anti-Id antibody

Levy JCO 2014


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Mayo Clinic – Lymphocyte recovery post ASCT

• Multiple studies, but effectors or specific subsets not identified

NHL – OS post ASCT HL – OS post ASCT

Porrata Blood 2002; Porrata BJH 2002


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Summary of the old era• Therapies are non-specific• Allogeneic transplant may be the ultimate

adoptive immunotherapy– But it comes with a potential price

• Other therapies (IFN, vaccines etc.) have more modest benefit– Immune responsiveness may be an important

concept– Disease specific (FL different than DLBCL

which is different than HL)


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Immunotherapy – a problem of definition

• Think of all of the therapy you give as standard of care “chemotherapy

• How much of it may be immune active?RituximabBrentuximabLenalidomideAutologous transplantation


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So in the new era…

• Checkpoint inhibitors• A host of other antibody approaches• Cell-based therapies• Combination strategies• Signaling pathway inhibitors (PI3K, BTK

as examples)

• What’s ready for prime time?


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Role of the Immune Checkpoint• We need the immune system to

fight pathogens and help eliminate abnormal cells

• We also need to have controls on this system– Maintain tolerance and prevent

injury to self tissue• The immune checkpoint is the

series of inhibitory signals for this system– While designed for self control,

these signals can be exploited by cancer cells

Pardoll , 2012, Nat Rev Can, 5, 252‐265

Cancer Cell T‐cell


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Pardoll , 2012, Nat Rev Can, 5, 252‐265

Cancer Cell T‐cell

Immune Checkpoint Blockade


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• PathologyofcHL:raremalignantReed‐Sternbergcellswithinanextensiveinflammatory/immunecellinfiltrate.

• Geneticanalyses:frequent9p24.1amplificationwithupregulation ofPD‐1ligandsandJAK2.

• Hypothesis:cHL mayhaveageneticallydrivendependenceonPD‐1.

Relevance of the Immune Checkpoint in Classical HL

Juszczynski et al PNAS 2007; 104: 13134Green et al Blood 2010; 116: 3268; Chen et al. Clin Cancer Res 2013;

19:3462


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Readyforprimetime…


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Nivolumab in Patients (Pts) With Relapsed or Refractory Classical Hodgkin Lymphoma

(R/R cHL): Clinical Outcomes From Extended Follow‐up of a Phase 1 Study (CA209‐039)

Stephen M. Ansell, MD, PhD,1 Philippe Armand, MD, PhD,2 John Timmerman, MD,3Margaret A. Shipp, MD,2 M. Brigid Bradley Garelick, MD,4 Lili Zhu, MS,5

Alexander M. Lesokhin, MD6

1Mayo Clinic, Rochester, MN, USA; 2Dana‐Farber Cancer Institute, Boston, MA, USA; 3Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA; 4Bristol‐Myers Squibb, Wallingford, CT, USA; 5Bristol‐Myers Squibb, Princeton, NJ, USA;

6Memorial Sloan Kettering Cancer Center, New York, NY, USAPresented at ASH 2015


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Compare and Contrast – 2 different PhaseII trials (at your peril)

Nivo PembroSchedule Q2Weekly Q2WeeklyToxicity 22% Grade 3 AE

No Grade 410% Grade 3 AENo Grade 4

ORR 87% 66%Time to Response 12W 12WPFS / DOR Median NR Median NR

Difficult to assess any differences at this pointNivolumab further ahead in development at this time (and has a published manuscript)


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PhilippeArmand1,JohnTimmerman2,AlexanderM.Lesokhin3,AhmadHalwani4,MichaelM.Millenson5,StephenJ.Schuster6,MartinGutierrez7,EmmaC.Scott8,

DeepikaCattry3,GordonJ.Freeman1,BjoernChapuy1,AzraH.Ligon9,ScottJ.Rodig9,LiliZhu10,JosephF.Grosso10,JasonSimon10,MargaretA.Shipp1,

AdamD.Cohen6,DanielLebovic11,MadhavDhodapkar12,DavidAvigan13,StephenM.Ansell14,IvanBorrello15

NivolumabinRelapsedorRefractoryLymphoidMalignanciesandClassicalHodgkinLymphoma:

UpdatedResultsofaPhase1Study

1Dana‐FarberCancerInstitute,Boston,MA;2JonssonComprehensiveCancerCenter,UniversityofCalifornia,LosAngeles,CA;3MemorialSloanKetteringCancerCenter,NewYork,NY;4UniversityofUtahHuntsmanCancerInstitute,SaltLakeCity,UT;5FoxChaseCancerCenter,Philadelphia,PA;6AbramsonCancerCenter,UniversityofPennsylvania,Philadelphia,PA;7JohnTheurerCancerCenter,HackensackUniversityMedicalCenter,Hackensack,NJ;8OregonHealthandScienceUniversity,Portland,Oregon;9Brighamand

Women’sHospital,Boston,MA;10Bristol‐MyersSquibb,Princeton,NJ;11UniversityofMichiganHematology,AnnArbor,MI;12YaleCancerCenter,NewHaven,CT;13BethIsraelDeaconessMedicalCenter,Boston,MA;14MayoClinic,Rochester,MN;15JohnsHopkinsUniversity

SchoolofMedicineandtheSidneyKimmelComprehensiveCancerCenter,Baltimore,MDEHA 20 TH CONGRES S

JUNE 2015V I ENNA , AUSTR IA


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Summary of anti-PD1 Ab Activity in Lymphoma

Agent Histology N ORR (%)

Nivo HL 23 87

Pembro HL 31 66

Nivo TCL 23 17

Nivo FL 10 40

Nivo DLBCL 11 36

Nivo PMBL 2 0 (2SD)

Pembro PMBL 10 40

Ansell ASH 2015, Armand ASH 2015, Armand EHA 2015, Zinzani ASH 2015


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Immunotherapy in Lymphoma -Summary

• Long history of usage of immune-based therapy in lymphoma– Frequently employed non-specifically

• Checkpoint inhibition is a specific targeted strategy that appears safe with promising activity– Development in NHL is less clear

• Biologic insights are needed– HL is an excellent paradigm


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Immunotherapy in Lymphoma –Conclusions

• PD1 inhibition is a new paradigm in the treatment of REL/REF HL– Appears to be new standard post brentuximab

failure• PD1 inhibition requires further development in

NHL– Biology and biomarkers needed

• Multiple new immunotherapies in development

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