BLOOD CANCERS

2016 update and relevant immunology basicsZeena Nackerdien

BLOOD CANCERS

From mature B cells─ Uncommon

Six types of HL, including one involving Reed-Steenberg cells

Subtypes include─ Nodular

sclerosis─ Mixed

cellularity CHL

From B cell/T cell progenitors, mature T/B cells, or NK cells

─ ~4% of all cancers in the USA

>61 Types Non-Reedberg-

Steenberg-cell disease = NHL

DLBCL is most common subtype

Often occurs in white blood cells, but can also occur in other types of cells

─ > common in clildren & teens

4 Types─ AML─ CML─ ALL─ CLL

Cancer of plasma cells in the bone marrow

─ Uncommon, but risk increases with age

Molecular cytogenetic classification of MM has been proposed by a working group

─ Trisomies and IgH translocations are the most common cytogenetic abnormalities

Flat with shadow

HL HL

NHL

Lk

ALL, Acute lymphocytic leukemia; CHL, Classical Hodgkin’s lymphoma; AML, Acute myelogenous leukemia; CLL, Chronic lymphocytic leukemia; CML, Chronic myelogenous leukemia DLBCL, Diffuse large B-cell lymphoma; HL, Hodgkin’s lymphoma; NHL,, Non-Hodgkin’s lymphoma; Lk, Leukemia; MM, multiple myeloma1. http://www.uptodate.com/contents/clinical-presentation-and-diagnosis-of-non-hodgkin-lymphoma?source=search_result&search=non-hodgkin%27s+lymphoma&selectedTitle=1~1502. http://www.cancer.org/cancer/non-hodgkinlymphoma/detailedguide/non-hodgkin-lymphoma-key-statistics; 3. Fonseca R, Bergsagel PL, Drach J, et al. Leukemia, 2009;23(12):2210-214. Rajan AM, Rajkumar SV. Blood Cancer J. 2015;5:e365.

MM

HODGKIN LYMPHOMA STATISTICS

% of all new US cancer cases in 2016: 0.5

% of all US cancer deaths in 2016: 0.2

Relative 5-year survival rate (2006-2012): 86.2%

1. National Cancer Institute. Surveillance, Epidemiology, and End Results Program. SEER Stat Fact Sheets 2016 . http://seer.cancer.gov/statfacts/html/hodg.html.

NON-HODGKIN LYMPHOMA STATISTICS

% of all new US cancer cases in 2016: 4.3

% of all US cancer deaths in 2016: 3.4

Relative 5-year survival rate (2006-2012): 70.7

1. National Cancer Institute. Surveillance, Epidemiology, and End Results Program. SEER Stat Fact Sheetshttp://seer.cancer.gov/statfacts/html/nhl.html..

LEUKEMIA STATISTICS

% of all new US cancer cases in 2016: 3.6

% of all US cancer deaths in 2016: 4.1

Relative 5-year survival rate (2006-2012): 59.7

1. National Cancer Institute. Surveillance, Epidemiology, and End Results Program: http://seer.cancer.gov/statfacts/html/leuks.html.

MYELOMA STATISTICS

% of all new US cancer cases in 2016: 1.8

% of all US cancer deaths in 2016: 2.1

Relative 5-year survival rate (2006-2012): 48.5%

1. National Cancer Institute. Surveillance, Epidemiology, and End Results Program. SEER Stat Fact Sheets. http://seer.cancer.gov/statfacts/html/mulmy.html..

What do we know about Hodgkin Lymphoma management?

How to Approach,

Workup, Stage&

individualize Treatmentof Hodgkin Lymphoma

HODGKIN LYMPHOMA: APPROACH The WHO defines 5 disease sub-types ie,  nodular sclerosing, mixed cellularity (see the image below), lymphocyte depleted, lymphocyte rich, and nodular lymphocyte-predominant. Up to 30% of cases of classical Hodgkin lymphoma may be positive for EBV proteins.

Differential diagnosis includes excluding any other disease presenting with lymphadenopathy and constitutional symptoms, other solid tumors and non-Hodgkin lymphoma

How do doctors diagnose the disease?

What is the workup?http://emedicine.medscape.com/article/201886-overview

HODGKIN LYMPHOMA: WORKUP Clinical and laboratory histories as well as accurate staging are workup fundamentals. Imaging (CT and PET scanning), sampling (biopsy and histologic findings), and an assessment of prognostic factors are required for staging.

Hematologic (complete blood cell [CBC] count) and blood chemistry studies may be non-specific, but remain valuable in mapping the extent of the disease.

What is the workup?

What are the disease stages??http://emedicine.medscape.com/article/201886-overview

HODGKIN LYMPHOMA: STAGING The Ann-Arbor classification system, mainly

citing lymph node involvement, is used to stage the disease.

• Stage I - A single lymph node area or single extranodal site

• Stage II - Two or more lymph node areas on the same side of the diaphragm

• Stage III - Lymph node areas on both sides of the diaphragm

• Stage IV - Disseminated or multiple involvement of the extranodal organs

What are the disease stages?

How do doctors treat the disease?http://emedicine.medscape.com/article/201886-overview

HODGKIN LYMPHOMA: TREATMENT Therapies Examples

Radiation Therapy (RT)

Involved-site RT

Induction Chemotherapy

ABVD regimen

Salvage Chemotherapy

Stanford V regimen

Autologous/Allogenic Stem Cell Transplantation

Patient/someone else’s bone marrow stem cells used.

How do doctors treat the disease?

…Overview/PrognosisAlthough the disease is considered curable.,treatment is associated with long-term toxicities and the potential for the development of resistance.

The following relative 5-year survival rates are associated with the respective localized, regional and metastatic states of the disease ie, 91.5%, 93.1%, and 77.3%.Menu

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ABVD regimen includes The ABVD regimen includes doxorubicin [Adriamycin], bleomycin, vinblastine, and dacarbazine); Stanford V regimen includes doxorubicin, vinblastine, mechlorethamine, etoposide, vincristine, bleomycin, and prednisone given in a 28-day cycle http://emedicine.medscape.com/article/201886-treatment; 2. http://emedicinhttp://emedicine.medscape.com/article/201886-overview

What do we know about Non-Hodgkin Lymphoma management?

How to Approach,

Workup, Stage&

individualize Treatmentof Non-Hodgkin

Lymphoma

NON-HODGKIN LYMPHOMA (NHL): APPROACH NHLs are clonal expansions of B cells

(85% of all NHLs) or T cells and/or NK cells (15% derived from T/NK cells) arising from an accumulation of lesions affecting proto-oncogenes or tumor suppressor genes, resulting in cell immortalization. The t(14;18)(q32;q21) translocation is the most common chromosomal abnormality associated with NHL.

Differential diagnosis includes excluding any other disease presenting with benign lymph node infiltration or reactive follicular hyperplasia secondary to infection

How do doctors diagnose the disease?

What is the workup?http://emedicine.medscape.com/article/203399-overview

DownloadKey NHL subtypes

NON-HODGKIN LYMPHOMA (NHL): WORKUP • Complete blood cell

(CBC) count

• Serum chemistry studies, including lactate dehydrogenase (LDH)

• Serum beta2-microglobulin level

• HIV serology

• Chest radiography

• Computed tomography (CT) scan of the neck, chest, abdomen, and pelvis

• Positron emission tomography (PET) scan

• Excisional lymph node biopsy

• Bone marrow aspirate and biopsy

• Hepatitis B testing in patients in whom rituximab therapy is planned because reactivation has been reported

• Other studies as needed

What is the workup?

What are the disease stages?http://emedicine.medscape.com/article/203399-overview

NON-HODGKIN LYMPHOMA (NHL): STAGING

What are the disease stages?

How do doctors treat the disease?

*A,B,X , and E sub-categories of stages:A: No fever, no exaggerated sweating and no weight loss are present;B: Fever, excessive sweating and weight loss are present;X: Bulky disease (large masses of lymphocytes) is present;E Category: The lymphoma has spread to areas or organs outside of the lymph nodes, or to tissues beyond, but near, the major lymphatic areas.https://www.lls.org/lymphoma/non-hodgkin-lymphoma/diagnosis/nhl-staging

More than half of all patients with intermediate or aggressive disease and more than 80 percent of all patients with indolent disease are diagnosed with stage III or IV NHL.

Stage*/Description

I – 1 lymph node group

II –≥ lymph node groups on same side of diaphragm

III – Lymph node groups on both sides of diaphragm

IV – ≥ organs other than lymph nodes & possible involvement of lymph nodes

NON-HODGKIN LYMPHOMA (NHL): TREATMENT Therapies Examples

Growth factor support

Granulocyte-colony stimulating factor 

Infusional Chemotherapy

eg, CHOP

Radiation Therapy (RT)

Involved-field RT 

Autologous/Allogenic Stem Cell Transplantation

Patient/someone else’s bone marrow stem cells used.

How do doctors treat the disease?

…Overview/PrognosisNHL treatment varies depending on tumor stage,phenotype (B-cell, T-cell or natural killer NK] cell/null-cell), histology (ie, low-, intermediate-, or high-grade), symptoms,performance status, patient age, and comorbidities

The following relative 5-year survival rates are associated with the respective localized, regional and metastatic states of the disease ie, 82.6%, 74.4%, and 63.1%.

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In Special Populations

CHOP: Prednisone, methotrexate, leucovorin, doxorubicin, cyclophosphamide, and etoposide—cyclophosphamide, etoposide, Adriamycin, cytarabine, bleomycin, Oncovin, methotrexate, leucovorin, and prednisone (ProMACE-CytaBOM); Methotrexate, bleomycin, doxorubicin (Adriamycin), cyclophosphamide, Oncovin, and dexamethasone (m-BACOD); Methotrexate-leucovorin, Adriamycin, cyclophosphamide, Oncovin, prednisone, and bleomycin (MACOP-B); RT, radiation therapy http://emedicine.medscape.com/article/203399-overviewhttp://seer.cancer.gov/statfacts/html/nhl.html

What do we know about Multiple Myeloma management?

How to Approach,

Workup, Stage&

individualize Treatmentof Multiple Myeloma

MULTIPLE MYELOMA(MM): APPROACH MM is usually defined byneoplastic

proliferation of plasma cells involving more than 10% of the bone marrow are clonal expansions of B cells. Patients with ≥ 60% clonal plasma cell involvement of the marrow, serum free light chain ratio of 100 or higher (provided involved free light chain level ≥ 100 mg/L), and/or greater than one focal lesion on MRI are defined as MM even in the absence of end-organ damage.

Differential diagnosis includes excluding any other condition eg, metastatic bone disease/monoclonal gammopathies of undetermined significance

How do doctors diagnose the disease?

What is the workup?http://emedicine.medscape.com/article/204369-overviewhttp://meetinglibrary.asco.org/content/159009-176

DownloadMM diagnostic criteria/related plasma cell disorders

MULTIPLE MYELOMA(MM): WORKUP • Serum and urine

assessment for monoclonal protein (densitometer tracing and nephelometric quantitation; immunofixation for confirmation)

• Serum-free light chain assay (in all patients with newly diagnosed plasma cell dyscrasias)

• Bone marrow aspiration and/or biopsy

• Serum β2-microglobulin, albumin, and lactate dehydrogenase measurement

• Standard metaphase cytogenetics

• Fluorescent in situ hybridization

• Skeletal survey

• Magnetic resonance imaging

What is the workup?

What are the disease stages?http://emedicine.medscape.com/article/204369-overview

MULTIPLE MYELOMA(MM): STAGING

What are the disease stages?

How do doctors treat the disease?

The Revised ISS combines elements of tumor burden & disease biology (± high-risk cytogenetic abnormalitiesa/LDH) to create a unified prognostic index.

Stage/Description

ISS Stage I – (Serum albumin > 3.5, serum β2-macroglobulin < 3.5 & no high-risk cytogenetics; Normal LDH

II – Neither Stage I/III

ISS Stage III– Serum β2-macroglobulin > 5.5 & high-risk* cytogenetics; Elevated LDH

*High-risk: [t(4:14), t(14;16), or del(17p)]aAbnormalities such as t(4:14), t(14;16), t(14; 20), gain 1(q), del(1p)or del(17p) influence disease course, response to therapy, and MM prognosisISS, International Staging System; LDH, lactate dehydrogenasehttp://emedicine.medscape.com/article/204369-overview Rajkumar SV. ASCO Educational Handbook. Updated Diagnostic Criteria and Staging System for Multiple Myeloma.2016. http://meetinglibrary.asco.org/content/159009-176.

MULTIPLE MYELOMA(MM): TREATMENT Treatment Examples

Initial Chemotherapy eg, Bortezomib/dexamethasone in non-transplant candidates

Adjunctive treatment Erythropoietin/Corticosteroids/Plasmapheresis/Surgery

Related bone diseasetreatment

Bisphosphonates, Zoledronic Acid

How do doctors treat the disease?

…Overview/PrognosisThe deepest response in the first round is sought with appropriate treatment; this should lead to better overall survival in transplant & non-transplant patients.

The following relative 5-year survival rates are associated with the respective Stage I, II and III disease stages ie, 82%, 62%, and 40%.

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http://emedicine.medscape.com/article/204369-overview; http://meetinglibrary.asco.org/sites/meetinglibrary.asco.org/files/edbook/176/images/EDBK_159009-table3.png

What do we know about AML management?

How to Approach,

Workup, Stage&

individualize Treatmentof Acute Myelogenous/

Myeloid Leukemia (AML)

AML: APPROACH AML is a life-threatening condition, occurring largely in older adults. Although a normal karyotype can be a hallmark of de novo myelodysplastic syndromes AML, tumors characteristically have 11q23 abnormalities involving the MLL gene. Secondary AML associated with other diseases are prone to relapse and exhibit resistance to chemotherapy.

Differential diagnosis includes ruling out other diseases eg, ALL, biphenotypic leukemia, chronic myelogenous leukemia blast crisis, and aplastic anemia.

How do doctors diagnose the disease?

What is the workup?https://online.epocrates.com/diseases/27411/Acute-myelogenous-leukemia/Key-HighlightsALL, acute lymphocytic leukemia; MLL gene, encodes histone-lysine N-methyltransferase 2A

Most common type ofacute leukemiain adults

AML: WORKUP A definitive diagnosis requires the presence of ≥ 20% blast cells in the bone marrow. Immunochemistry and histological methods are critical to establish the myeloid origin of the leukemia. Tests may include:

• Physical exam/medical history

• CBC with differential

• Peripheral blood smear

• Coagulation panel

• Lumbar puncture

• HLA typing

• Imaging

• Molecular and immunophenotyping

What is the workup?

What are the disease stages?https://online.epocrates.com/diseases/27431/Acute-myelogenous-leukemia/Diagnostic-ApproachCBC, Complete Blood Cell count; HLA, human leukocyte antigen

AML: STAGING

What are the disease stages?

How do doctors treat the disease?

French, American, and British researchers (FAB) as well as the WHO have devised separate stagingcriteria.

FABWHO

• AML with certain genetic abnormalities• AML with myelodysplasia-related changes• AML related to previous

chemotherapy/radiation• AML, not otherwise specified

• MO: Undifferentiated AML• M1: AML + minimal maturation• M2: AML + maturation• M3: APML• M4: AMML• M4eos: AMML + eosinophilia• M5: Acute monocytic leukemia• M6: Acute erythroid leukemia• M7: Acute megakaryoblastic leukemia

APML, acute promyelocytic leukemia; AMML, acute myelomonocytic leukemia; WHO, World Health Organization; http://www.cancer.org/cancer/leukemia-acutemyeloidaml/detailedguide/leukemia-acute-myeloid-myelogenous-classified

SummaryIn the case of FAB staging, subtypes M0 through M5 all start in immature forms of white blood cells. M6 AML starts in very immature forms of red blood cells, while M7 AML starts in immature forms of cells that make platelets. See complete WHO staging system description here.

AML: TREATMENTTreatment* will depend on patient age, fitness, disease type (presumptive or acute AML/acute promyelocytic leukemia (APML). 1st/2nd/3rd-line/adj. therapies may include:

How do doctors treat the disease?

Menuhttp://emedicine.medscape.com/article/204369-overviewhttp://seer.cancer.gov/statfacts/html/amyl.html

AML, < 60 y or ≥ 60 y Relapsed /refractory AML/APMLAPML

• Induction CT• Intrathecal cytarabine• Postinduction

consolidation CT• Stem cell transplant• Low-dose subcutaneous

CT

• Induction CT:tretinoin + an anthracycline

• Supportive care• Consolidated

/maintenanceCT• Cessation of drug +

corticosteroid• Intrathecal cytarabine

• Clinical trial eval. or salvage CT + stem cell transplant + supportive care (AML, <60 y)

• Clinical trial eval. ± stem cell transplant/reinduction reg.

(AML, ≥60 y) • Salvage therapy+ Stem cell

transplant+Supportive care (APML)

Adj., adjuvant; CT, chemotherapy; eval., evaluation; reg., regimen

Overview/Prognosis (US statistics for 2006-2012) Rates for new AML cases have been rising on average 3.4% over the last decade. Relative 5-year survival rate for this cancer is 26.6%.

What do we know about CLL management?

How to Approach,

Workup, Stage&

individualize Treatmentof Chronic Lymphocytic

Leukemia (CLL)

CLL: APPROACH This chronic lymphoproliferative disorder accounts for up to 30% of all leukemias in the USA. Although it has different manifestations, the disease is identical to the mature (peripheral) B cell neoplasm small lymphocytic lymphoma (SLL), one of the indolent non-Hodgkin lymphomas. A CLL precursor is called monoclonal B lymphocytosis.

Differential diagnosis includes ruling out other diseases eg, FL, Hairy Cell Leukemia, Splenic Marginal Lymphoma.

How do doctors diagnose the disease?

What is the workup?http://emedicine.medscape.com/article/199313-differentialhttp://www.uptodate.com/contents/clinical-presentation-pathologic-features-diagnosis-and-differential-diagnosis-of-chronic-lymphocytic-leukemia?source=search_result&search=chronic+lymphocytic+leukemia&selectedTitle=4~150

ALL, Acute Lymphocytic Leukemia;; CLL, chronic lymphocytic leukemia; FL, Follicular Lymphoma.

Most common type ofchronic leukemiain adults

AML: WORKUP • Microscopic examination

• Clonality confirmed by flow cytometry

• Serum immunoglobulin level quantitation

• Serum-free light chain assays

• Bone marrow aspiration and biopsy

• Liver/spleen ultrasonography

• Chromosomal Testing

What is the workup?

What are the disease stages?http://emedicine.medscape.com/article/199313-workup

CLL: STAGING

What are the disease stages?

How do doctors treat the disease?

The Rai-Sawitsky (USA) and Binet (Europe) systems have been used to classify disease stages.

http://emedicine.medscape.com/article/199313-workup#c9

Rai-Sawitsky

Low risk (formerly stage 0) – Lymphocytosis in the blood and marrow only (25% of presenting population)

Intermediate risk (formerly stages I and II) – Lymphocytosis with enlarged nodes in any site or splenomegaly or hepatomegaly (50% of presentation)

High risk (formerly stages III and IV) – Lymphocytosis with disease-related anemia (hemoglobin <11 g/dL) or thrombocytopenia (platelets <100 x 10 9/L) (25% of all patients)

Binet

Stage A – Hemoglobin greater than or equal to 10 g/dL, platelets greater than or equal to 100 × 10 9/L, and fewer than 3 lymph node areas involved

Stage B – Hemoglobin and platelet levels as in stage A and 3 or more lymph node areas involved

Stage C – Hemoglobin less than 10 g/dL or platelets less than 100 × 10 9/L, or both

CLL: TREATMENT

How do doctors treat the disease?

…Overview/PrognosisThe estimated number of new cases for 2016 is 18,960. Relative US 5-year survival rates (2006-2012) were 82.6%.

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Patients with low-risk, stable diease (Binet A) require only periodic follow-up. Rapid disease progression warrant chemotherapies ranging fromnucleoside analogs to biologics. Symptoms include:• Weight loss of more than 10% over 6 months• Extreme fatigue• Fever related to leukemia for longer than 2 weeksIn addition, allogeneic stem cell transplantation is the only known curative therapy. Pneumococcal and influenza vaccinesare needed (patients are prone to common and unusualInfections).

http://emedicine.medscape.com/article/199313-treatment#d1http://seer.cancer.gov/statfacts/html/clyl.html

EMERGING THERAPIESTargeted agents and Immunotherapies

IMMUNE CHECKPOINT AXIS: NEW TREATMENTS

CD-27

PD-1/PD-L1

TIM-3

CTLA-4

4-1BB (CD137) LAG-3

OX40

CD40L

• Ipilimumab• Tremelimumab

Anti-PD1• Nivolumab• Pembrolizumab• Pidilizumab• AMP-224

Anti-PD-L1• Avelumab

(MSB0010718C)• MEDI4736• MEDL3280A• BMS-936559

• Urelumab (BMS-663513)• PF05082566

• Varlilumab (CDX-1127)Immune-checkpoint inhibitors target the inhibitory signals transduced through the PD 1– PD L1 axis and CTLA 4 interactions ‑ ‑ ‑

Agonist• Dacetuzumab• Chi Lob 7/4• CP-870893

Inhibitory receptors/Blocking antibodies

Activating receptors/Agonistic/Antagonistic antibodies

MED16469

Antagonist• Lucatumumab

CTLA 4, cytotoxic T lymphocyte-associated protein 4; ‑ ‑PD 1, programmed cell death protein 1; ‑PD L1, programmed cell death 1 ligand 1 ‑Batlevi CL, Matsuki E, Brentjens RJ, Younes A. Nat Rev Clin Oncol. 2016;13(1):25-40.

T cells recognize antigens presented on the MHC by the TCR. The fate of T cells upon antigen recognition is determined by the additional ligand–receptor interactions between the T cells and APCs (or tumor cells). The co-stimulatory signals activated via CD28,4-1BB (CD137), OX40, and CD27 promote activation of T cells, whereas those sent via CTLA-4 and PD-1 decrease T-cell activation. Various treatment modalities are being developed to modulate these signals.

CLINICAL EFFICACY OF IMMUNE CHECKPOINT INHIBITORS

ORR (%)

B NHL‑

DLBCL

FL

T NHL‑

HL

PR (%)CR (%) ResponseDuration*SD (%)

26

36

40

17

87

10

18

10

0

26

16

18

30

17

61

52

27

60

43

13

NA

22 weeks

Not reached

NA

NA

Nivolumab

*Median Duration of Response ; B, B-cell; CR, Complete Response; DLBCL, Diffuse Large B-cell Lymphoma; FL, Follicular Lymphoma; HL, Hodgkin Lymphoma; NHL, Non-Hodgkin Lymphoma; PR, Partial Response; ORR, Overall Response Rate; OS, overall survival; PFS, Progression-free Survival; SD, Stable Disease; T, T-cellBatlevi CL, Matsuki E, Brentjens RJ, Younes A. Nat Rev Clin Oncol. 2016;13(1):25-40.

PFS: 86% at 24 weeks

OS: median not reached

CLINICAL EFFICACY OF IMMUNE CHECKPOINT INHIBITORS

ORR (%)

HL

DLBCL

FL

T NHL‑

HL

PR (%)CR (%) ResponseDuration*SD (%)

66 21 45 21 Not reached

Pembrolizumab

*Median Duration of Response ; B, B-cell; CR, Complete Response; HL, Hodgkin Lymphoma; PR, Partial Response; ORR, Overall Response Rate; SD, Stable Disease; T, T-cellBatlevi CL, Matsuki E, Brentjens RJ, Younes A. Nat Rev Clin Oncol. 2016;13(1):25-40.

CLINICAL EFFICACY OF IMMUNE CHECKPOINT INHIBITORS

ORR (%)

B-NHL

HL(post allo

SCT)

PR (%)CR (%) ResponseDuration*SD (%)

11.1

14.3

5.6

0

5.6

14.3

NA

NA

NA

NA

Ipilimumab

*Median Duration of Response ; B, B-cell; CR, Complete Response; HL, Hodgkin Lymphoma; NHL, Non-Hodgkin Lymphoma; PR, Partial Response; ORR, Overall Response Rate; SD, Stable Disease; T, T-cellBatlevi CL, Matsuki E, Brentjens RJ, Younes A. Nat Rev Clin Oncol. 2016;13(1):25-40.

CHIMERIC ANTIGEN RECEPTORS (CAR) FEATURESCARs consist of an extracellular antigen-recognition domain and a signaling domain that provides ‘signal 1’ to activate T cells (1st-generation CARs). Co-signaling domain providing ‘signal 2’ is present in 2nd-generation CARs. Two co-stimulatory signaling domains are present in 3rd-generation CARs.

First-generation

Second-generation

Third-generation

Antigen-recognition domains

SignalingDomainsSignal 1

Signal 1

Signal 1

Signal 2 Signal 2

Jackson HJ, Rafiq S, Brentjens RJ. Nat Rev Clin Oncol. 2016;13(6):370-83.

CAR-T CELL TARGETS FOR THE TREATMENT OF HEMATOLOGIC MALIGNANCIES

Your Logo

Target• CD22• CD20• ROR1• Ig• CD30• CD123• CD33• LeY• BCMA• CD138

Structure• CD3 and CD28• CD3 or CD3 & 4 1BB‑• CD3 and 4 1BB‑• CD3 and CD28• CD3 and CD28• CD3 and CD28• CD3 and CD28• CD3 and 4-1BB• CD3 and CD28• CD3 and 4-1BB

Malignancy• FL, NHL, DLBCL, B ALL‑• CD20+-malignancies• CLL, SLL• CLL, low grade B cell malignancies‑ ‑• HL, NHL• AML• AML• AML• MM• MM

Does not include CD19 targets. AML, acute myeloid leukemia; B ALL, B cell acute lymphoblastic leukaemia; BCMA, B cell maturation antigen; CLL, chronic ‑ ‑ ‑lymphocytic leukaemia; DLBCL, diffuse large B cell lymphoma; FL, follicular lymphoma; HL, Hodgkin lymphoma; LeY, Lewis Y antigen; MM, multiple myeloma; NHL, ‑non Hodgkin lymphoma; ROR1, inactive tyrosine protein kinase transmembrane receptor ROR1; SLL, small lymphocytic lymphoma‑ ‑Jackson HJ, Rafiq S, Brentjens RJ. Nat Rev Clin Oncol. 2016;13(6):370-83.

APPROACHES TO IMPROVING CAR-T TREATMENT

CAR, chimeric antigen receptor; IL-12, inerleukin-12; NK, natural killer; NKG2, natural-killer-cell-recognition domain;Jackson HJ, Rafiq S, Brentjens RJ. Nat Rev Clin Oncol. 2016;13(6):370-83.

e.g. infusion of tumour-targeted CAR- T cells together withB-cell-specific CAR-T cells

CAR-T cell

Armored CARs

Dual-receptor

chemokines/CARs

NK cell-receptor

CARs

Combination Therapies

B-cell eradication

Targetingtumor

vasculaturee.g. VEGFR-2-specific CAR-T cells

e.g. IL-12-secreting CAR-T cells

e.g. CAR T cells co-expressing tumour-specific CAR and chimeric cytokine receptor 4β

e.g. NKG2-based CAR

e.g. CAR-T cells and checkpoint blockade

SIDE EFFECTS: CYTOKINE RELEASE SYNDROME ETC.

SYMPTOMS1. Hypotension, vascular leak, coagulopathy, cytopenia2. Respiratory/renal insufficiency3. Myalgia, fevers4.Neurological complications, including dyphasia,confusion, delirium, visual hallucinations, seizure-likeactivity

DIAGNOSTICS1. C reactive protein‑2. Ferritin

TREATMENT/MANAGEMENT1. Vasopressors2. Ventilatory support3. Corticosteroids4. Anti IL 6 receptor antibody (tocilizumab) therapy‑ ‑5. Supportive care

Jackson HJ, Rafiq S, Brentjens RJ. Driving CAR T-cells forward. Nat Rev Clin Oncol. 2016;13(6):370-83.

Different “off-switches” eg, genes & drugs are being tested

to mediate serious cytotoxicities

Antibody-drug conjugate targeting CD30 eg, Brentuximab

vedotin Brentuximab vedotin and augmented ICE (ifosfamide, carboplatin, etoposide) prior to autotransplant

PET-adapted sequential salvage therapy with

brentuximab vedotin followed by augmented ICE Panobinostat

OTHER EMERGING HL TREATMENTS (RELAPSED/REFRACTORY/SALVAGE THERAPIES)

HL, Hodgkin Lymphomahttp://www.managinghodgkinlymphoma.com/melanoma/faq-library/117-what-new-emerging-treatments-for-relapsed-refractory-hl-are-most-likely-to-improve-patient-outcomeshttp://www.ascopost.com/issues/april-15-2014/better-options-emerging-for-salvage-therapy-in-hodgkin-lymphoma.aspx

PI3K inhibitor eg, Idelalisib

Btk inhibitors eg, Ibrutinib

Syk inhibitors eg, fostamatinib

BCL-2 inhibitors eg, Venetoclax

Anti-CD20 monoclonal antibodies eg, obinutuzumab

Antibody-drug conjugates

EZH2 inhibitors

OTHER EMERGING B-CELL NHL TREATMENTS

NHL, Non-Hodgkin Lymphoma; EZH2, the catalytic subunit of the polycomb repressor 2 complex; PI3K, phosphatidyl-inositol-3-kinase; Syk, spleen tyrosine kinase Cheah CY, Fowler NH, Wang ML. Annals of Oncology. 2016 (e-pub).

Quizartinib: FLT3 inhibitor

ASP-2215: FLT3 inhibitor with activity against TKD resistance mutation

AG-221: IDH2 inhibitor

AG-120: IDH1 inhibitor

ABT-199: BCL-2 inhibitor

OTHER EMERGING AML TREATMENTS

ASCO Educational Handbook. Emerging Therapies for Acue Myeloid Leukemia. Progress at Last?: http://meetinglibrary.asco.org/content/161258-176

The most targeted protein is FLT3 because of its role as the most common recurrent genetic alteration in patients with de novo AML. FLT3 internal tandem duplications occur in 30% of AML cases, and portend a poor prognosis, especially in patients with a high allelic

ratio.

Cyclin-dependent kinase inhibitors

BCL-2 inhibitors

Heat shock protein 90 inhibitors

Histone deacetylase inhibitors

Small modular immunopharmaceuticals

EMERGING REFRACTORY CLL TREATMENTS

http://www.medscape.com/viewarticle/756581_9http://www.onclive.com/insights/cll-2015/emerging-treatments-for-chronic-lymphocytic-leukemia

The selective BCL2 inhibitor venetoclax (ABT-199) has demonstrated significant results as both a single agent and in combination with rituximab (Rituxan). The primary side effect for venetoclax is tumor lysis syndrome, which must be carefully managed in the first 4 to 6 weeks of administration. Duvelisib is a phosphoinositide-3 (PI3)-kinase delta inhibitor that differs from the current FDA-approved PI3-kinase inhibitor idelalisib (Zydelig) in that duvelisib also inhibits the gamma isoform of PI3 kinase. This could potentially affect T-cells and myeloid cells. Ublituximab (TG-1101) is a novel monoclonal antibody that targets CD20 and may potentially have superior ADCC vs. other anti-CD20 antibodies.

ElotuzumabCarfilzumab

Pomalidomide

Panobinostat

Ixazomib

Anti-CD38antibodies

EMERGING MM TREATMENTS

http://www.onclive.com/publications/oncology-live/2015/june-2015/new-paradigm-emerging-in-multiple-myeloma-therapy?p=1Zagouri F, Terpos E, Kastritis E, Dimopoulos MA. Expert Opinion on Emerging Drugs. 2016;21(2):225-37.

Amongst emerging antibodies, elotuzumab which targets

SLAMF-7 and daratumumab which targets CD38, have

been recently approved by FDA for patients with

relapsed/refractory MM. Both agents are well tolerated.

Multiple clinical trials incorporating these

monoclonal antibodies in MM treatment are currently

ongoing

IMMUNITYBasics

IMMUNITY BASICS• Two cooperative defense responses

against pathogens– Non-specific/innate immunity– Specific/acquired/adaptive immunity

• Hematopoietic stem cells give rise to myeloid & lymphoid lineages

• Myeloid lineage includes:– Thrombocytes– Erythroid cells– Granulocytes (most abundant cells in

normal peripheral blood)– Monocytes

• Lymphoid lineage includes:– Lymphocytes

. Lebman D. Lippincott Illustrated Reviews Flash Cards: Immunology (First Edition). Wolters Kluwer; 2016.

Granulocytes are the most abundant cells in normal peripheral blood

WHITE BLOOD CELLS

Neutrophil

Eosinophil

Basophil Neutrophil

Monocyte

Lymphocyte

WHITE BLOOD CELLS: NEUTROPHILS

Approximately 50 to 80% of all white blood cells are neutrophils.These cells stain pink or purple-blue when using neutral dyes.The bone marrow has large reservoir that can be mobilized in response to an infection/inflammation.

1. Lebman D. Lippincott Illustrated Reviews Flash Cards: Immunology (First Edition). Wolters Kluwer; 20162 https://www.britannica.com/science/neutrophil.

WHITE BLOOD CELLS: EOSINOPHILS

Eosinophils make up less than 1% of white blood cells.These cells contain large granules and a nucleus, as seen by acid stains (eosin).Eosinophils play roles in mediating certain allergic reactions. IL-5 is linked to a specific allergic response and stimulates eosinophil growth.Abbreviations: IL-5, interleukin 51. Lebman D. Lippincott Illustrated Reviews Flash Cards: Immunology (First Edition). Wolters Kluwer; 20162. https://www.britannica.com/science/eosinophil

WHITE BLOOD CELLS: BASOPHILS

Basophils make up ~0.4% of white blood cells.Histological characteristics can be determined with a basic stain.Mediates hypersensitive reactions of the immune system.

1. Lebman D. Lippincott Illustrated Reviews Flash Cards: Immunology (First Edition). Wolters Kluwer; 20162 https://en.wikipedia.org/wiki/White_blood_cell3. https://www.britannica.com/science/basophil

WHITE BLOOD CELLS: MONOCYTES

Monocytes are the largest blood cells (15-18 µm) and make up ~7% of white blood cells.Cells are types of phagocytes ie, surround and kill microbes, ingest foreign materials, remove dead cells, and boost immune responses.1. Lebman D. Lippincott Illustrated Reviews Flash Cards: Immunology (First Edition). Wolters Kluwer; 20162. https://www.britannica.com/science/blood-biochemistry/Red-blood-cells-erythrocytes#toc257811

WHITE BLOOD CELLS: LYMPHOCYTES

Lymphocytes make up ~20 to 40% of white blood cells.Two primary cell types, T and B cells, originate in the thymus and bone marrow, respectively. These cells comprise “immunologic memory,” ie, a rapid response to a 2nd encounter with the same antigen. 1. Lebman D. Lippincott Illustrated Reviews Flash Cards: Immunology (First Edition). Wolters Kluwer; 20162. https://www.britannica.com/science/lymphocyte

WHITE BLOOD CELLS: LYMPHOCYTES

Human natural killer (NK) cells, the 3rd member of the lymphoid lineage, are large granular lymphocytes. These cells outnumber B cells by 3 to 1. The three cell types contribute to antiviral responses. Different types of T cells are referred to as helpers/killers. Uncontrollable growth of lymphocytes can result in blood cancers. The most common blood cancer is lymphoma.1. Lebman D. Lippincott Illustrated Reviews Flash Cards: Immunology (First Edition). Wolters Kluwer; 20162. https://www.britannica.com/science/lymphocyte3. Caligiuri MA. Human natural killer cells. Blood. 2008;112(3):461-9.

T cell

B cell

NK cell

ANTIBODY STRUCTURE

InterchainDisulfidebonds

Antigen binding

BiologicalActivity

mediationInterchainDisulfidebonds

Fab

Fc

𝑉𝐻

𝑉 𝐿

𝐶𝐻

𝐶𝐿

Light-chain Hypervariable regions

Heavy-chain Hypervariable regions

2

𝐶𝐻 3 VL and VH: variable regionsCL and CH: constant regions

Complement-binding region

Carbohydrate

MHC protein

Processed viral

antigen Interleukin -

1Helper T

cell T cell receptor that fits the particular antigen

Virus

Macrophage

Antigen – presenting cell

Cytotoxic T cell

Proliferation

MHC protein

Viral antigen

Infected cell

destroyed by

cytotoxic T cell

Interleukin - 2

T CELL

B CellAntibod

ies

Secretion

Plasma cell

B – cell receptor (BCR)

B cell

Mitosis and Differentiation

Lymphokines

Helper T cell

Tumour cell

NK CellApoptosi

s

Necrosis

Fas (CD9

5)

Fasl (CD95L)

NK cell

Perforin

ADCC

FcR Ag

Ab

Granzyme B

Granzyme

Perforin

Granzymerelease

Perforinpore

Targetcell

Endocytosis

Granuleexccytosis

Receptor

CTL

Target Cell For CTL

CREDITS• Slides 47-59: slideteam.net