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SLIDE 1

9/21/2016 1 A New Plan of Attack: Immunotherapy in Hematologic Malignancies

Katie Culos, PharmD BCOP Adult Stem Cell Transplant Clinical Pharmacist Vanderbilt University Medical Center

Conflict of Interest

• I have no professional/financial disclosures to report

Objectives

1) Discuss the principles of immunotherapy use in hematologic malignancies 2) Review the data supporting the current FDA‐approved agents to treat hematologic malignancies 3) Describe chimeric antigen receptor (CAR) T‐cell therapy approaches under clinical development 4) Explain the common toxicities and management strategies of immunotherapy in hematologic malignancies

Immunogenicity of Cancer

• Immunotherapy has eradicated hematologic malignancies with allogeneic hematopoietic cell

transplant (allo HCT)

• Use of alloreactive T‐cells to control recipient malignancy
• Also target non malignant cells and cause graft versus host disease (GVHD)
• Limitations to extending allo HCT to wider ranges of hematologic conditions

Antigenic Tumors:

• Secrete antigens

recognized by host‐ immune system eliciting an immune response Displayed:

• Spontaneous regression
• f primary lesions
• Histological evidence T‐

cell infiltration in early melanoma

• Increased incidence in

immunosuppressed patients Tumor evasion:

• Induction of immune

tolerance

• Resistance to

immune effector cells

Guerry D et al. J Invest Dermatol. 1993 Mar;100(3):342S‐345S. Welniak LA et al. Annu Rev Immunol. 2007;25:139‐170.

Monoclonal Antibody (mAb) Therapy

• Antibodies designed to bind with specific target tumor antigens

▫ Easy to produce as secreted proteins in mammalian cell culture ▫ Off‐the‐shelf reagents with high protein stability ▫ Used to treat a wide range of patients with hematologic cancers ▫ Offer a less toxic immune‐mediated treatment approach

• Rituximab was the first U.S. Food and Drug Administration (FDA) approved

mAb in 1997

▫ Approval based on Phase II study (Maloney et al.)  37 relapsed low‐grade or Follicular Non Hodgkin Lymphoma (NHL) patients  Intent to treat response rate of 46%  17 responses (3 CR, 14 PR)

Weiner LM et al. Nat Rev Immunol 2010;10:317‐327 Maloney DG et al. Blood 1997;90:2188‐2195 CR: complete response, PR: partial response

SLIDE 2

9/21/2016 2 mAbs

• 28% of Phase III cancer research pipeline
• None shown to cure cancer as single agent due to limitations in

their mechanisms of action including: ▫ Redundancy of molecular pathways leading to cancer cell survival ▫ Effects of the microenvironment ▫ Suboptimal interaction with effector cells due to alternative Fc glycosylation or Fc receptor polymorphism ▫ Activation of inhibitory receptors, and competition with circulating IgG

http://www.antibodysociety.org Chames et el. Mabs. 2009 Nov‐Dec;1(6): 539‐547

Bispecific T‐Cell Engagers (BiTE)

• The BiTE antibody transiently

creates a cyto‐lytic synapse between a cytotoxic T‐cell and the cancer target cell

• Can differ in size and specificity of

antigens recognized

• Most researcher use the CD3

complex on host T‐cells ▫ Expressed on all lymphocytes ▫ Engagement activates T‐cells

https://upload.wikimedia.org/wikipedia/commons/4/40/BiTE_antibody_en.svg Dreier et al. Int J Cancer. 2002 Aug 20;100(6):690‐7.

BiTE

• Following activation, apoptosis occurs via perforin‐mediated membrane

disruption of the cancer by the T cells

• Granules containing granzymes and the pore‐forming protein, perforin, fuse

with the T‐cell membrane and discharge their toxic content leading to the death of the target cell

http://mutated‐unmuated.blogspot.com/2011_06_01_archive.html

BiTE

• Sustained activation, proliferation, and cytotoxicity of T cells

as long as target cells are available

• Lack of cross resistance to commonly used forms of

chemotherapy = effective in treatment refractory patients with aggressive forms of leukemia and lymphomas

• Target cell‐dependent and mediated by polyclonal

lymphocytes ▫ Do not drive off ‐target immune response to self ▫ T‐cell‐mediated autoimmune disorders have not been

• bserved

Dreier et al. Int J Can 2002;100:690‐697 Handgretinger et al. Leukemia 2011;25:181‐184

Blinatumomab (Blincyto™)

• BiTE antibody which links CD3 on T‐cells to CD19 on B‐cells

resulting in a cyto‐lytic synapse and CD19 B‐cell death

• CD19 is a B cell‐restricted cell surface antigen expressed on

normal and malignant B cells ▫ Exception of hematopoietic stem cells (HSC) and terminally differentiated plasma cells

• Granted Accelerated FDA Approval December 2014
• Indication: Treatment of patients with relapsed or refractory,

Philadelphia chromosome negative, precursor B‐cell acute lymphoblastic leukemia (ALL)

BLINCYTO [package insert]. Thousand Oaks, CA; Amgen, Inc. December, 2014.

SLIDE 3

9/21/2016 3

Blinatumomab Phase 2 Dose‐Finding Trial

• Open‐label, multicenter, exploratory, single‐arm, phase II study that enrolled 36 patients

from German centers

• Step‐up dosing from 5‐30 mcg/m2 per day

Exclusion Criteria Ph+ ALL eligible for dasatinib or imatinib History or presence of CNS pathology Active CNS leukemia GVHD or immunosuppression for GVHD within 1 week of start of therapy Active infections Immunotherapy within 4 weeks or chemo within 2 weeks of start Neutralizing human anti‐murine antibodies

Topp MS, et al. J Clin Oncol. 2014;32(36): 4134‐4140.

Inclusion Criteria >5% bone marrow blasts Primary refractory disease or relapse after induction and consolidation chemo or after allo HCT ECOG performance status ≤2 Life expectancy ≥ 12 weeks Response to Treatment Response

• No. (N=36)

% CR/CRh 15/10 69 PR 2 6 Hypocellular BM 3 8 Refractory 4 11 Not evaluable 2 6 MRD Response

• No. (N=25)

% Across cycles 22 88 End of cycle one 18 72 End of cycle two 3 12 End of cycle three 1 4 No MRD response 3 12

Results

Topp MS, et al. J Clin Oncol. 2014;32(36): 4134‐4140. CR: complete response, CRh: CR with partial hematologic recovery, PR: partial response, BM: bone marrow, MRD: minimal residual disease

Results Cont.

• RFS (N=25) 7.6 months
• Median OS 9.8 months

▫ No prior allo HCT (N=21): 14.1 months ▫ Prior allo HCT (N=15): 8.8 months  P=0.201

• Of the 25 patients who achieved

CR or CRh: ▫ 13 proceeded to HSCT while still in remission

Topp MS, et al. J Clin Oncol.2014; 32(36): 4134‐4140. RFS: relapse free survival, OS: overall survival

• Open‐label, multicenter, single‐arm, phase II study that enrolled

189 patients from European and US centers

• Dosing: 9 mcg/day x 1 week, 28 mcg/day week 2‐4

Topp MS, et al. The Lancet. 2015;16:57‐66.

Exclusion Criteria

Ph+ ALL, Burkitt’s leukemia, ALL in testes or CNS, history of malignant disease within 5 years History or presence of CNS pathology Auto HSCT within 6 weeks; allo within 3 months Active infections, autoimmune disease, acute GVHD or chronic GVHD grade 2‐4 Chemo, radiotherapy, systemic GVHD treatment within 2 weeks Immunotherapy or investigational antileukemic drug within 4 weeks

Inclusion Criteria

>10% bone marrow blasts Primary refractory disease after induction or relapsed within 12 months after first CR or allo HCT, or not responded to or relapsed after first salvage or later ECOG performance status ≤2 Ph‐ B‐precursor ALL

SLIDE 4

9/21/2016 4

Response to Treatment Response CR or CRh during the first two cycles 81/189 43% No response to therapy 90/189 48% Not evaluable 18/189 10% Allo HCT after CR or CRh 32/81 40% MRD response during first two cycles 60/73 82%

Results

• Median overall survival (N=189): 6.1

months

• Relapse free survival (N=82): 5.9

months

• Prognosis and RR

▫ CR 73% in pts with < 50% bone marrow blasts ▫ CR 29% in pts with > 50% bone marrow blasts

Topp MS, et al. The Lancet. 2015;16:57‐66.

• Premeds:

▫ Dexamethasone 20 mg IV 1 hour prior to initiation each cycle ▫ Prior to dose titration ▫ Any time the infusion is stopped >4 hours

• Will run as 24 hour bag (10 mL/hr) or 48

hour bag (5 mL/hr)

• Must use dedicated lumen
• Do not flush infusion lines, particularly

when changing infusion bags or at completion of infusion

• Do not infuse with other medications
• IV bag volume will be more than the

volume administered to the patient ‐ do not empty the bag

Cycle 2 ‐ 5 28 mcg/day continuous infusion for 28 days Cycle 1 (D8‐28) 28 mcg/day continuous infusion Cycle 1 (D1‐7) 9 mcg/day continuous infusion

Administration

BLINCYTO [package insert]. Thousand Oaks, CA; Amgen, Inc. December, 2014.

Cyto‐Reduction

Topp MS, et al. J Clin Oncol. 2014;32(36): 4134‐4140. Topp MS, et al. The Lancet. 2015;16:57‐66.

High Risk Patients:

• >50% blast in bone

marrow

• >15000 blast

peripheral blood and elevated LDH Treatment Options:

• Dexamethasone up

to 24 mg for up to 5 days and/or Cyclophosphamide 200 mg/m2 for up to 4 days

• Dexamethasone

10‐24 mg/m2 for up to 5 days

Other BiTEs

• The first BiTE for the treatment of patients with acute myeloid

leukemia (AML ) is the CD33/CD3 construct called AMG 330

▫ Myeloid marker CD33 is an attractive target, as it is expressed on greater than 90% of AML cells ▫ Of clinical relevance, epigenetic modifier drugs (such as azacitidine) were found to increase CD33 on some AML cells and, in turn, augmented AMG 330‐induced cytotoxicity

Walter RB. Expert Rev Hematol. 2014 Jun;7(3):317‐9. De Propris MS et al. Haematologica. 2011 Oct;96(10):1548‐51.

Immune‐Checkpoint Axis

• Serves to maintain self‐tolerance and prevent autoimmunity
• The Immune synapse formed between antigen presenting cells

(APCs) and T‐cells is controlled by many co‐stimulatory and inhibitory interactions to modulate the intensity and duration

• f T‐cell activation
• Tumor and/or non‐tumor cells commonly overexpress

inhibitory proteins to suppress T‐cell effector functions and promote immune escape of the tumor ▫ Cytoxic T‐lymphocyte‐associated‐protein‐4 (CTLA‐4) ▫ Programmed cell‐death protein 1 (PD‐1)

Pardoll et al. Nat Rev Cancer 2012;12:252‐264

SLIDE 5

9/21/2016 5 CTLA‐4

• Expressed on T‐cells in the lymph nodes
• T‐cell activation through T‐cell receptor (TCR) signaling and CD28 co‐

stimulation mobilizes intracellular pool of CTLA‐4 to relocate to the T‐cell surface

• CTLA‐4 binds with CD80/86 and terminates CD28 co‐stimulation and T‐cell

activation

Linsley, P. S. et al. Immunity 4, 535–543 (1996). Linsley, P. S. et al. Immunity 1, 793–801 (1994). Batlevi CL et al. Nat Rev Clin Oncol. 2016 Jan;13(1):25‐40.

PD‐1

• Expressed on peripheral T‐cells
• T‐cell activation through recognition of ligands on tumor cells then leads

to transcription of PD‐1 and expression on T‐cell surface

• Subsequent engagement of PD‐1 with it ligands PDL‐1/PDL‐2 antagonizes

PI3K activity blocking T‐cell activation

Parry, R. V. et al. Mol. Cell Biol. 25, 9543–9553 (2005). Batlevi CL et al. Nat Rev Clin Oncol. 2016 Jan;13(1):25‐40.

FDA Approved Immune Checkpoint Inhibitors

• Anti‐PD‐1 monocolonal antibody

▫ Nivolumab (Opvdivo ™) ▫ Pembrolizumab (Keytruda™)

• Anti‐CTLA monocolonal antibody

▫ Ipilimumab (Yervoy ™)

Drake CG et al. Nat Rev Clin Oncol. 2014 Jan;11(1):24‐37. Lexi‐comp

Hodgkin Lymphoma

• 10 % of all malignant lymphomas
• Current cytotoxic treatment regimens 80% cure rate
• Resistant/Relapse on first line treatment autologous

hematopeotic stem cell transplant (auto HCT) ▫ However has not shown to improve overall survival ▫ Progression post auto HCT have very poor outcomes and novel treatment strategies are needed

NCCN Guidelines Hodgkin Lymphoma. Version 2016.3 Younes A et al. Semin Hematol. 2016 Jul;53(3):186‐9.

Hodgkin lymphoma

• Two subtypes:

▫ Classical hodgkin (cHL) 95% ▫ Nodular lymphocyte‐predominant 5%

• cHL is characterized by large CD30 malignant Hodgkin and Reed

Sternberg (HRS) cells

• HRS = 1% of tumor cells found surrounded by a variety of

inflammatory cells ▫ provide immunosuppression, survival and growth support

• HRS cells express high levels of PD1 ligands, PD‐L1 and PD‐L2
• Over expression of PDL‐1/PG‐L2 inhibits the intra‐tumoral T‐cell

response directed at malignant cells

Brockelmann P. et al Leuk Lymphoma. 2016 Sep;57(9):2014‐24. Younes A et al. Semin Hematol. 2016 Jul;53(3):186‐9.

SLIDE 6

9/21/2016 6

PD‐1 blockade with nivolumab in relapsed

• r refractory Hodgkin lymphoma
• Phase 1 dose‐escalation study and expansion cohort
• Relapsed/refractory cHL patients

▫ Dose of 1 mg/kg and escalated up to 3 mg/kg

• Max tolerated dose not reached
• Expansion cohort (n=23) received 3 mg/kg at week 1, week 4, and then

every 2 weeks until disease progression or complete response or for a maximum of 2 years ▫ Primary objective: evaluate the safety and side‐effect profile ▫ Secondary objectives: characterizing the efficacy and assessing PD‐1 ligand loci integrity and expression of the encoded ligands

Ansell et al. N Engl J Med. 2015 Jan 22;372(4):311‐9

Results

Relapsed post ASCT 78% Relapsed post‐brentuximab therapy 78% Adverse Event (AE) of any type 78% Grade 3 AE 22% Overall response 87% Complete response 17% Partial Response 70% Stable Disease 13% PFS @24 weeks 86%

• 11 patients continued therapy and recent reports have confirmed responses have

been durable

Ansell et al. N Engl J Med. 2015 Jan 22;372(4):311‐9

Nivolumab

• On May 17, 2016 FDA granted accelerated approval
• Indication: Treatment of patients with classical Hodgkin lymphoma (cHL)

relapsed/progressed after auto HCT and post‐HCT brentuximab vedotin

• Efficacy was evaluated in 95 patients

▫ 65% ORR (95% CI: 55%, 75%), with 58% partial remission and 7% complete remission ▫ Median time‐to‐response was 2.1 months (range: 0.7 to 5.7 months)

• Safety was evaluated in 263 patients

▫ Most common (reported in at least 20%) adverse reactions of any grade were:  Fatigue, upper respiratory tract infection, cough, pyrexia, and diarrhea ▫ The most common SAEs, reported in 1% to 3% of patients were:  Pneumonia, pleural effusion, pneumonitis, pyrexia, infusion‐related reaction, and rash ▫ Immune‐mediated adverse reactions occurring in 1% to 5% of patients, included:  Rash, pneumonitis, hepatitis, hyperthyroidism, and colitis

http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm501412.htm

Nivolumab Post Allo HCT

• No published experience regarding safety and efficacy of nivolumab after allo

HCT

• Significant concerns about safety of PD1 Immune inhibitors after allo HCT due

to increased GVHD severity and mortality ▫ Animal models show PD1 ligands heavily expressed in tissue with GVHD affected mice compared to GVHD‐free mice ▫ PD1/PD‐L1 blockage exacerbates acute and chronic GVHD

• FDA issued a “Warning and Precaution” for complications of nivolumab after

allo HCT ▫ Transplant‐related deaths have occurred ▫ Monitor closely for early evidence of transplant‐related complications such as:  Hyperacute GVHD, severe acute GVHD, steroid‐requiring febrile syndrome, hepatic veno‐occlusive disease and other immune‐mediated adverse reactions

Saha A, et al. Blood. 2013;122:3062–73\J Fujiwara H, et al. Immunol. 2014;193:2565–73. http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm501412.htm

Programmed Death‐1 Blockade With Pembrolizumab in Patients With Classical Hodgkin Lymphoma After Brentuximab Vedotin Failure

• Phase 1b trial
• Relapsed/refractory cHL patients

▫ Dose of 10 mg/kg every 2 weeks until disease progression

• ccurred
• 31 patients enrolled
• Principal endpoints were safety and complete remission rate

Armand et al. J Clin Oncol. 2016 Jun 27. pii: JCO673467.

Results

Relapsed post ASCT 71% Relapsed post‐brentuximab therapy 100% Adverse Event (AE) of any type 97% Grade 3 AE 16% Overall response 65% Complete response 16% Partial Response 48% Stable Disease 23% PFS @24 weeks 69% PFS @52 weeks 46%

• ≥ Grade 3 AEs in 16% pts, no treatment related deaths

Armand et al. J Clin Oncol. 2016 Jun 27. pii: JCO673467.

SLIDE 7

9/21/2016 7 Hodgkin Lymphoma

• Per National Comprehensive Cancer Network (NCCN)

guidelines 2106.3 Nivolumab and Pembrolizumab both options for cHL with relapsed/refractory disease

• Ongoing trials incorporating PD‐1 antibodies and

brentuximab vedotin, and in combination with chemotherapy

NCCN Guidelines Hodgkin Lymphoma. Version 2016.3 Brockelmann P. et al Leuk Lymphoma. 2016 Sep;57(9):2014‐24.

Other Hematologic Malignancies

Liu J et al. Blood. 2007;110:296–304 Lesokhin AM, et al Blood.2014;124:291. Yang H, et al. Leukemia. 2014;28:1280–8.

Multiple Myeloma

• PD1 and PDL1 are expressed on surface of malignant plasma cells and

lymphocytes in tumor microenvironment

• Nivolumab trial showed no response in 27 multiple myeloma patients,

however 18/27 (67%) had stable disease which may justify more testing

Myeloid Malignancies (MDS, AML, CMML)

• PD1, PDL1 and CTLA‐4 expressed at rates of 15%, 34% and 8%
• Recent study showed PD1/PDL1 expression is regulated by DNA methylation

as well as MDS blasts treated with decitabine saw overexpression of genes encoding proteins involved in PD1/PDL1 immune checkpoint

• Combination treatment with demethylating agents and PD1 blockage could

have activity in MDS patients

Other Hematologic Malignancies cont.

Kiyasu J, et al. Blood. 2015;126:2193–201. Dorfman DM, et al. Am J Surg Pathol. 2006;30:802–10. Lesokhin AM, et al Blood.2014;124:291.

Diffuse Large B‐Cell Lymphoma

• PD‐L1 + associated with significant decreased OS

Follicular Lymphoma

• Does not usually express PD1/PD‐L1, however PD1 expressing

lymphocytes are detectable in the tumor microenvironment

• Phase 1 nivolumab trial included 10 FL patients
• 1 CR, 3 PR, 6 SD
• PFS at 6 months 68%

CAR T‐Cell

• First CAR T‐Cell discovered in 1989
• Autologous T‐lymphocytes genetically modified to combine the

advantage of: ▫ Human leukocyte antigen (HLA)‐ independent antigen recognition ▫ Cytotoxic ability of T‐cells

• No CAR‐T cell therapies FDA approved all experience in the setting
• f a clinical trial

Namuduri M et al. Expert Rev Hematol. 2016 Jun;9(6):511‐3.

CAR T‐cells in Action

http://blogs.shu.edu/cancer/files/2015/11/CD19‐CAR.jpg

SLIDE 8

9/21/2016 8 CAR T‐cell Development

• 1st Generation: Single‐chain variable fragment of an antibody specific for tumor antigen linked

to the intracellular signaling domain of the TCR ▫ Lacked significant antitumor activity most likely due to inadequate t‐cell persistence

• 2nd/3rd Generation: added 1 (CD28/4‐1BB) or 2 (CD28/4‐1BB /OX40) co‐stimulatory domains
• Most display significant clinical activity
• 4th Generation: “armored CAR” combine a second‐generation CAR with the addition of various

genes, including cytokine and co‐stimulatory ligands, to enhance the tumoricidal effect

• Early in clinical testing

Batlevi CL et al. Nat Rev Clin Oncol. 2016 Jan;13(1):25‐40. Till, B et al. Blood. 2008;112, 2261–2271. Wang, J. et al. Hum. Gene Ther. 2007; 18, 712–725. Pegram, HJ et al. Cancer J. 2014; 20, 127–133.

CD 19 Antigen

• Attractive target due to:

▫ Presence in the vast‐majority of b‐ cells  95% of NHL ▫ Expressed throughout b‐cell development  Wider range of b‐cells to target than with CD20  Immature progenitor cells may be cause of relapse in mature b‐cell malignancies ▫ Depletion restricted to lymphoid system  B‐cell aplasia not necessary life‐ threatening

• Most investigations conducted in

CD19 positive hematologic malignancies such as: ▫ B‐cell Acute Lymphoblastic Leukemia (B‐ALL) ▫ Chronic lymphocytic lymphoma (CLL) ▫ Follicular Lymphoma (FL) ▫ Diffuse Large B‐cell Lymphoma (DLBCL) ▫ Mantle Cell Lymphoma (MCL)

Ghorashian S, et al. Br J Haematol 2015;169: 463‐478. Kim SJ. Korean J Hematol. 2011; 46: 211‐213. Kim SM,et al. Blood 2014; 124: 1622.

Car T‐Cell Generation & Administration

1. Leukoapheresis of patients peripheral blood mononuclear cells (PBMCs) 2. T cells are activated and selected by incubation with anti‐CD3 and ant‐CD28 paramagnetic beads 3. Activated T‐cells transduced with retro/lentiviral vectors carrying the CAR construct 4. Cells expanded 1,000 fold over a 1‐2 week period 5. CAR T‐cells infused into patient over 1‐2 day period

Batlevi CL et al. Nat Rev Clin Oncol. 2016 Jan;13(1):25‐40. https://www.junotherapeutics.com/our‐science/scientific‐platform/Car T‐Cell Process

CAR T‐Cell Clinical Experience

• Numerous distinctions between trials by various

groups including:

▫ scFvs derived from separate hybridomas ▫ Disparate signaling domains (CD28 vs. 4‐1BB) ▫ Genetic modification methodology ▫ Dose/preparative regimen prior to cell infusion ▫ T‐cell dose

Namuduri M et al. Expert Rev Hematol. 2016 Jun;9(6):511‐3.

B‐ALL

Institution CAR Design Pt Population Outcome Toxicity Phase

MSKCC CD28/CD3ζ

• n=32 adults
• R/R B‐ALL

91% CR

• B‐cell aplasia
• CRS
• Phase I

UPenn/CHOP 4‐1BB/CD3ζ

• n=30

children and young adults

• B‐ALL

90% CR

• B‐cell aplasia
• CRS
• Phase I/II

NCI CD28/CD3ζ

• n=20

children and young adults

• B‐ALL

70% CR

• B‐cell aplasia
• CRS
• Phase I

Fred Hutchinson 4‐1BB/CD3ζ

• n=20 adults
• B‐ALL

83% CR

• CRS
• Phase I/II

CHOP, Children’s Hospital of Philadelphia; CR, complete response; CRS, cytokine‐release syndrome; Fred Hutchinson, Fred Hutchinson Cancer Research Center; MSKCC, Memorial Sloan Kettering Cancer Center; NCI, National Cancer Institute Park JH et al. Blood. 2014; 124, A382. Maude, S.L et al N. Engl. J. Med. 2014; 371, 1507–1517. Lee, DW et al. Lancet. 2015; 385, 517–528. A382. Turtle, CJ, et al. Blood. 2014;124, a384.

CLL

MSKCC CAR Design Pt Population Outcome Toxicity Upenn/CHOP 4‐1BB/CD3ζ

• N=23 adults
• CLL

22% CR 17% PR

• CRS in all

responding pts NCI CD28/CD3ζ

• n=4 adults
• CLL

25% CR 50% PR 25% SD MSKCC CD‐28/CD3ζ

• n=7 adults
• B‐ALL, CLL

29% CR 43% PR 15% SD

• Mild CRS in

3pts

Porter, DL et al. Blood. 2014; 124, a1982. Kochenderfer, JN et al. Blood. 2012; 119, 2709‐2720. Park, JH et al. J. Clin. Oncol. 2014;32 (5s Suppl.), a7020. CHOP, Children’s Hospital of Philadelphia; CR, complete response; CRS, cytokine‐release syndrome; Fred Hutchinson, MSKCC, Memorial Sloan Kettering Cancer Center; NCI, National Cancer Institute; PR, partial response; SD, stable disease

SLIDE 9

9/21/2016 9 Other B‐cell Malignancies

Institution CAR Design Pt Population Outcome Notes MSKCC CD‐28/CD3ζ

• N=6
• Aggressive B‐cell

NHL 100% CR

• Used Auto

HCT

• CRS in 30%

UPENN/CHOP 4‐1BB/CD3ζ

• N=8
• DLBCL, FL, MCL

38% CR 12.5 PR

• CRS in 15

pts NCI CD28/CD3ζ

• n=11
• DLBCL, indolent

lymphoma, CLL 55% CR 33% PR 11% SD

• CRS in 75%

pts with CR with DLBCL Fred Hutchinson CD28/CD3ζ

• N=9
• NHL

11% CR 55% PR

• No severe

CRS

Sauter, C. S. et al. Blood.2014; 124, a677. Schuster, SJ et al. Blood. 2014; 124, a3087. Kochenderfer, JN et al. J. Clin. Oncol.2015;33, 540–549. Turtle, CJ. et al. ]. Blood. 2014; 124, a384. CHOP, Children’s Hospital of Philadelphia; CR, complete response; CRS, cytokine‐release syndrome; Fred Hutchinson, Fred Hutchinson Cancer Research Center; MSKCC, Memorial Sloan Kettering Cancer Center; NCI, National Cancer Institute; PFS, progression free survival; PR, partial response;

What we learned so far..

• Co‐stimulatory domains

▫ 4‐1BB vs. CD28

 ALL  4‐1BB seems more durable CAR T‐cell persistence  4‐1BB exhibits great MRD‐CRs  Unsure of the effect on OS/EFS  CLL/B‐NHL  Heterogenous patient population limits comparison on co‐stimulatory domain

• Conditioning chemotherapy

▫ Lymphodepleting chemo can enhance CAR T‐cell responses by eradication of regulatory T‐cells and other immune cells ▫ Higher peak CAR T‐cells recorded in trials with fludarabine + cyclophosphamide vs. cyclophosphamide conditioning alone

• T‐cell dose

▫ Suggested correlation between cell dose and dose‐limiting toxicity, CRS, however optimal dose still unknown

Porter DL, et al. Sci Transl Med.2015;7(303):303ra139. Turtle CJ, et al. Blood. 2015;126(23):184. Maude, S.L et al N. Engl. J. Med. 2014; 371, 1507–1517. Gattinoni L, et al. J Exp Med. 2005;202(7):907‐912.

Novel CAR T‐Cells

CD22

• FL, NHL, ALL Large cell

lymphoma

• Ongoing Phase 1

CD20

• MCL, FL, DLCBL
• Trials ongoing with

decent responses reported

CD30

• HL, NHL
• Studies under

development

https://clinicaltrials.gov/ct2/show/ NCT02315612 (2015). https://clinicaltrials.gov/ct2/show/ NCT00621452 (2014). https://clinicaltrials.gov/ct2/show/ NCT01316146 (2016).

Blinatumomab Adverse Reactions

Immunologic

Febrile neutropenia (25%) Cytokine Release Syndrome (11%)

Gastrointestinal

Nausea (25%) Constipation (20%) Diarrhea (20%)

Infectious

Bacterial (19%) Fungal (15%) Viral (13%) Other (44%)

Miscellaneous

Pyrexia (62%) Peripheral edema (25%) Hypokalemia (23%) Headache (36%)

• Misc. Cont.

Insomnia (15%) Cough (19%) Dyspnea (15%) Tremor (20%) Rash (21%) BLINCYTO [package insert]. Thousand Oaks, CA; Amgen, Inc. December, 2014.

Blinatumomab Black Box Warning

• May be life‐threatening or fatal, occurred in

patients receiving Blincyto; interrupt or discontinue Blincyto as recommended

Cytokine release syndrome (CRS)

• May be severe, life‐threatening or fatal, occurred

in patients receiving Blincyto; interrupt or discontinue Blincyto as recommended

Neurotoxicity

• Hospitalization recommended for first 9 days of Cycle 1 and first 2 days of

Cycle 2

BLINCYTO [package insert]. Thousand Oaks, CA; Amgen, Inc. December, 2014.

SLIDE 10

9/21/2016 10 Blinatumomab CRS

• Activation of T‐Cells leads to production of supra‐physiologic levels of

cytokines that trigger a temporary and reversible systemic inflammatory state ▫ Occurred in 2‐6% of blinatumomab study patients ▫ Highest elevation of cytokine release was in first 48 hours of infusion initiation ▫ Severe presentation associated with high blasts counts, which may warrant prior cyto‐reduction ▫ Not associated with clinical response

• Sign/Symptoms: pyrexia, headache, nausea, asthenia, hypotension,

increased LFTs, increased Tbili, Disseminated intravascular coagulation (DIC), capillary leak syndrome (CLS), and hemophyagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS)

BLINCYTO [package insert]. Thousand Oaks, CA; Amgen, Inc. December, 2014. Klinger M et al. Blood. 2012;119:6226–6233.

Blinatumomab Neurotoxicity

• Thought to be induced by transient neuro‐inflammatory irritations of

the CNS ▫ All events were reversible when withholding blinatumomab infusion

• r applying dexamethasone
• Occurred in ~50% of study patients

▫ Elderly patients had an increased rate of neurotoxicity compared to patients < 65 years ▫ Median time to onset 7 days

• Most common manifestations: Headaches (36%) and tremors (~20%)

▫ > Grade 3 toxicities (~15%)  Encephalopathy, convulsions, speech disorders, disturbances in consciousness, confusion and disorientation, and coordination and balance disorders ▫ Seizures (~1.5%)

BLINCYTO [package insert]. Thousand Oaks, CA; Amgen, Inc. December, 2014.

Dose Reductions for Toxicity

Toxicity Grade* Action

CRS Grade 3 Withhold drug until resolved. Restart at 9mcg/d and escalate to 28 mcg/d after 7 days if the toxicity does not reappear Grade 4 Discontinue blinatumomab permanently. Neurological Seizure Discontinue permanently if more than one seizure occurs. Grade 3 Withhold until no more than Grade 1 for at least 3 days. Restart at 9mcg/d and escalate to 28 mcg/d after 7 days if the toxicity does not reappear. If toxicity returns or does not resolve in 7 days, discontinue. Grade 4 Discontinue blinatumomab permanently. Other Grade 3 Withhold until no more than Grade 1 for at least 3 days. Restart at 9mcg/d and escalate to 28 mcg/d after 7 days if the toxicity does not reappear. If toxicity returns or does not resolve in 14 days, discontinue. Grade 4 Consider discontinuing blinatumomab permanently. *Based on the Common Terminology Criteria for Adverse Events (CTAE)

BLINCYTO [package insert]. Thousand Oaks, CA; Amgen, Inc. December, 2014.

CAR T‐Cell Toxicity

• Not associated with the infusion of the cells, rather

with the expansion and persistence

• Most notable toxicities:

▫ CRS

 Severed CRS

▫ CNS toxicity ▫ B‐cell aplasia

Lee, DW et al. Lancet. 2015; 385, 517–528. A382.

• Fevers
• Hypotension
• Capillary Leak syndrome
• Respiratory distress
• Neurologic disturbances

Clinical CRS

• Liver Function Tests
• Ferritin
• Triglycerides
• Hypo‐fibrinogenemia
• Interferon‐gamma
• Interluekin‐6
• Soluble IL‐2Rα
• IL‐10
• C‐Reactive Protein (CRP)

Biochemical CRS (elevated)

Davila ML, et al. Sci Transl Med. 2014;6(224):224ra225. Grupp SA, et al. N Engl J Med. 2013;368(16):1509–1518. Hylton et al. Biol Blood Marrow Transplant 21 (2015) S355eS373

CAR T‐Cell CRS

• Occurs within 1‐3 weeks of infusion
• Incidence 18‐100%
• Elevated CRP with clinical symptoms

can be a biomarker for severe CRS, incidence 27‐53%

• Severe CRS Definition
• Persistent fevers >38 celcius
• Clinical derangements
• Hypotension with 1 pressor
• Hypoxia PO2<90% and or

neurological disturbances

• Select cytokine elevations
• At least 1 cytokine with max fold

change of at least 250 or 2 with max fold change of at least 75

SLIDE 11

9/21/2016 11 CAR T‐Cell CRS

• Numerous algorithms for treatment
• Supportive care for hypotension, respiratory, etc.
• Pressors, oxygen, fluids, anti‐pyretics, broad spectrum antibiotics
• Tocilizumab
• IL‐6‐receptor‐blocking monoclonal antibody
• Ameliorate CRS and preserve CAR T‐cell function
• Dose: 4‐8 mg/kg (max dose 800mg) X 1, wait 4‐6 hrs for resolution of

symptoms may repeat x 1

• Steroids
• Reserved for tocilizumab refractory CRS due to risk of blunting CAR T‐

cell effect

• Dexamethasone 10 mg IV q6h x 3 days

Hylton et al. Biol Blood Marrow Transplant 21 (2015) S355eS373 Hylton et al. Biol Blood Marrow Transplant 21 (2015) S355eS373

CAR T‐Cell CNS Toxicity

• Incidence as high as 50%
• Unknown if CAR T‐cells cross into CNS, believe

neurotoxicity secondary to an inflammatory state rather than direct affect on neural tissue

• Symptoms

▫ Confusion, delirium, word‐finding aphasia, coma, seizures ▫ May require intubation for airway protection

• Most studies start seizure prophylaxis

▫ Keppra 500 mg q12h

Namuduri M et al. Expert Rev Hematol. 2016 Jun;9(6):511‐3.

“Off‐target/off‐tumor toxicities”

• B‐cell aplasia

▫ Incidence 86‐100% ▫ Can last for weeks to months ▫ IVIG replacement can supplement hypogammaglobinemia and reduce infection risk ▫ Hypothesized as a surrogate marker for CAR T cell persistence

Namuduri M et al. Expert Rev Hematol. 2016 Jun;9(6):511‐3.

Immune‐Related Adverse Events

• To be covered in afternoon Immunotherapy session

A New Plan of Attack: Immunotherapy in Hematologic Malignancies

Katie Culos, PharmD BCOP Adult Stem Cell Transplant Clinical Pharmacist Vanderbilt University Medical Center