Targeted Therapies in Hematologic Malignancies

Transcription

1 Targeted Therapies in Hematologic Malignancies Patricia A Mangan, RN, MSN, APRN-BC Abramson Cancer Center University of Pennsylvania Philadelphia, Pa January 27, 2017

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3 Targeted Therapies in Blood Cancers Tyrosince Kinase Inhibitors Imatinib mesalyte Second generation TKIs: Disatinib (Sprycel) Nilotimib (Tasigna) Ibrutinib (BTK) Idelalisib FLT 3 inhibitors Tandutinib Sorafenib Suntitinib Quizartinib (AC220) BiTEs Blinatumomab Monoclonial Antibodies Rituxan (CD20) Brentuximab (CD30) Daratuzumab (CD38) Elotuzumab (SLAMF7) PD-1 Inhibators Permbrotuzumab Chimeric Antigen Receptor (CAR-T) CART 19 (ALL, CLL,NHL,MM) BCMA CAR (MM) CART 128 (AML)

4 Chronic Myeloid Leukemia (CML): The Philadelphia Chromosome Defined by single molecular entity: BCR/ABL

5 Cytogenetic Abnormality of CML: The Ph Chromosome

6 Bcr-Abl Signal Transduction Pathways Bcr-Abl (Phosphorylates multiple substrates) JAK/STATs BCL-2 inhibition of apoptosis MYC GRB2 CRKL CBL (p120 Cbl ) RAS -Leads to malignant expansion of myeloid cells -Stimulation of mitosis Paxillin (Adhesion) PI-3 kinase RAF-MEK-MAPK cascade regulates cell cycle progression and differentiation -Disrupts regulatory control by stroma -Inhibits apoptosis Actin (Adhesion)

7 TKIs: Tyrosine Kinase Inhibitors in Ph+ leukemias Tyrosine kinase inhibitor: Imatinib mesylate (Gleevec) approved in nd Generation tyrosine kinase inhibitors: Dasatinib (Sprycell) (2006/2007) Nilatinib (Tasigna) (2007/2010) 3 rd Generation tyrosine Ponatinib (Iclusig) T315I-positive CML

8 Ibrutinib Ibrutinib (Imbruvica) FDA approved in 2013/2014 for MCL and CLL and Waldenstroms macroglobulinemia oral selective and covalent inhibitor of the enzyme Bruton tyrosine kinase (BTK) Ongoing studies in DLCBL and multiple myeloma Can cause: thrombocytopenia, rash, diarrhea, fatigue, cough, bruising, constipation

9 Idelalisib (Zydelig) Oral tryosine-kinase inhibitor targeting PI3- Kinase Delta Approved in 2014 for treatment of CLL/SLL and FL lymphomas Causes rapid lymph node shrinkage, along with an increase in lymphocytosis, prior to inducing objective responses in CLL patients S/E: can be significant Liver toxicities Sever diarrhea and colitis Pneumonitis and pulmonary infiltrates

10 Venetoclax BCL-2 inhibitor indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion who have received at least one prior therapy 2016 approval Tumor Lysis Syndrome, anemia, neutropenia, diarrhea, nausea, anemia, upper respiratory tract infection, thrombocytopenia, and fatigue, febrile neutropenia, fever, autoimmune hemolytic anemia

11 FLT3 Inhibitors fms-like tyrosine kinase (FLT3) is a type III receptor tyrosine kinase in the PDGF family of growth factor receptors FLT3 is one of the most commonly mutated genes in AML 24% in adult AML, 10% in pediatric AML Tandutinib Sorafenib Sunitinib Quizartinib (AC220)

12 Monoclonal Antibodies: Rituximab Antigen Targets on B-Cells IgG antibody to CD20 Induces apoptosis Depletes B cells from peripheral blood, lymph nodes, and bone marrow Does not affect stem cells May CD20 expression Broad indication in NHL 375 mg/m 2 IV by a variety of schedules IgG = immunoglobulin G; ADCC = antibody dependent cell-mediated toxicity; IV = intravenous. BC Cancer Agency, 2009; Rituxan prescribing information, 2008; Fu et al, 2008.

13 Brentuximab Brentuximab vedotin is a chimeric monoclonal antibody (mouse/human) targeting CD30 CD30 is commonly expressed in Hodgkins lymphoma and anaplastic large cell lymphoma FDA approved for relapsed or refractory Hodgkin's lymphoma and relapsed or refractory systemic anaplastic large cell lymphoma (2011)

14 Brentuximab Potential S/E PN Neutropenia and thrombocytopenias PML (progressive multifocal leukoencephalopathy) rare and usually fatal progressive white matter disease caused by JC virus Nausea Rash Upper resp. infection

15 New Multiple Myeloma Targeted Therapies and Nursing Implications Category Agents Key Nursing Considerations Monoclonal antibodies Elotuzumab (SLAMF7) Daratumumab (anti CD38) Infusion reaction Premedicate Type and Screen issues PD 1 Inhibitors Pembrotuzumab Pembro/Pom/Dex Pembro/Rev/Dex

16 Checkpoint Inhibitors: What is PD-1? Is an immune check point regulating the immune system by preventing the activation of T-cells, promoting self tolerance target (PD-1)/programmed cell death protein ligand 1 (PD-L1) interactionspd-1 and its ligands negatively regulate immune responses (T cell response) Many cancer cells make PD-L1, which inhibits T cells from attacking the tumor. When PD-L1 is blocked from binding with PD-1 the T cell to work.

17 Pembrolizumab (Keytruda) humanized antibody used in cancer immunotherapy targets the programmed cell death 1 receptor. (PDL-1 inhibitor) The drug was initially used in treating metastatic melanoma and other solid tumor malignancies Now used in hematologic malignancies: HD and Multiple Myeloma

18 BiTEs bispecific T cell engagers

19 Blinatumomab a constructed monoclonial antibody known as bispecific T cell engagers (BiTEs) exert action selectively and directs the human immune system to act against tumor cells Blinatumomab targets CD19 FDA approved 12/2014 for treatment of relapsed refractory Ph- B cell

20 Blinatumomab: Potential Side Effects Flu-like symptoms - fever - headache - fatigue Tremor Weight increase Hypokalemia Decrease of blood immunoglobulin CNS - Seizure - Encephalopathy - Tremor - Apraxia - Speech disorders - Disorientation

21 Rationale for Cellular Immunotherapy 1. Novel agents and autosct extend survival but progression is common 2. T and NK cells from myeloma patients can kill autologous myeloma cells ex vivo 3. DLI (donor lymphocyte infusion) demonstrates graft-versusmyeloma (GVM) effect usually associated with GVHD 4. Allogeneic SCT may cure myeloma high mortality with full Novel agents (-imid s, proteasome inhibitors) ASCT myeloablation Barlogie et al. J Clin Oncol 2006; Kroger N, Blood 2004; Crawley, Blood 2005; Spisek R et al. J Exp Med. 2007; Noonan K et al, Cancer Res 2005; Krishnan A et al Lancet Oncology 2013)

22 Chimeric Antigen Receptor Gene transfer technology is used to stably express CARs on T cells, conferring novel antigen specificity CARs combine Antigen recognition domain (Anti-CD19) with intracellular signaling domain Intracellular signaling domain: same functionality as endogenous T cells (Anti-CD19) Co-stimulatory endodomain mediates potent antileukemia effects & promotes persistence Milone, et al. Mol Ther 2009 Carpenito, et al. PNAS 2009

23 2nd Generation CAR for B Cell Malignancy: Autologous T Cells Transduced w/ Anti-CD19 Receptor Spliced to TCRzeta and 4-1BB Signaling Domains 4-1BB 4-1BB Lentiviral vector to deliver construct CD3-z and 4-1BB signaling domains augments proliferation and survival Three new CAR improvements tested in CLL and ALL * UPCC04409, ClinicalTrials.gov #NCT Anti-CD3/anti-CD28 mab coated bead stimulation (artificial DC)

24 Overview of CAR T cell therapy Courtesy of D. Porter

25 CD19: An ideal tumor target CD19 is expressed on the surface of most B cell malignancies Antibodies against CD19 inhibit growth of tumor cells CD19 expression is restricted to B cells and their precursors CD19 is not expressed on pluripotent bone marrow stem cells On target expected SE is B cell aplasia preb-all B cell lymphomas and leukemias myelomas Stem Cell pro B pre B immature B mature B plasma cell CD19 CD22 CD20 1. Scheuermann RH, et al. Leuk Lymphoma. 1995;18: Image adapted from Janeway CA, Travers P, Walport M, et al. Immunobiology. 5th ed. New York, NY: Garland Science; 2001: ; Scheuermann RH, et al. Leuk Lymphoma. 1995;18: ; and Feldman M, Marini JC. Cell cooperation in the antibody response. In: Roitt I, Brostoff J, Male D, eds. Immunology. 6th ed. Maryland Heights, Missouri: Mosby;2001:

26 Chimeric antigen receptor- background Combines recognition domain of antibody with signaling domain of T cell Uses gene transfer (eg. lentiviral vector) to stably express CAR on T cells confers novel antigen specificity Addition of co-stimulatory domains (CD28, 4-1BB/CD137) augments proliferation and survival Garfall et al, Discovery Med 2014

27 CD19-targeted CAR T cells for B cell malignancies Results published from 8 trials 27 ongoing/planned trials at 10 centers autologous and allogeneic T cells Responses seen in heavily-pretreated CLL, ALL, and B-cell NHL ORR 40-50% in CLL, 80% in ALL many durable CRs > 3 years Relapses do occur: CD19 negative or loss of CAR T cells Toxicities: tumor lysis syndrome B cell aplasia / hypogammaglobulinemia Cytokine release syndrome persistent high fevers, rigors, myalgias, hypotension, hypoxia, neurologic dysfunction, HLH/macrophage activation syndrome very high IL6, also IFN-gamma, TNF, Ferritin responds to steroids but lose CAR T cells tocilizumab (anti-il6 receptor mab) can abrogate CRS Davila et al, Science Trans Med 2014; Porter et al, ASH 2013; #873; Maus et al, Blood 2014

28 Pilot Study of CART19 in Multiple Myeloma Initial Auto-SCT Pre-Enrollment Course TTP#1 (eligible if <1y) Progression/ Relapse Therapy for Relapse (+/-) Pilot study of 10 patients Progression within one year of prior ASCT Age <70 Fit for 2 nd ASCT Primary endpoint: safety & feasibility Secondary endpoints: CTL019 engraftment Aplasia of normal B cells High-dose Melphalan/ Auto-SCT + CTL019 (W/I 2 weeks) TTP#2 Progression/ Relapse Cytokine release syndrome ASCT toxicities Cognitive dysfunction Hypogammaglobulinemia Time-to-progression measured against prior time-to-progression ( remission inversion ) Correlation of outcome with multiple myeloma CD19 expression

29 CART 19 in Myeloma (CTL019): Preliminary Results Phase 1 trial 10 Patients treated 6 patients with on going responses No significant toxicities or deaths seen One patient with a sustained complete molecular remission MRD negative scr >1year

30 IgA (mg/dl) Pilot Study of CTL019 in Advanced Multiple Myeloma: Pt Mel 140 ASCT # Mel 200 ASCT #1 Progression by IMWG Criteria CART19 Day Transplant Day

31 IgA (mg/dl) Pilot Study of CTL019 in Advanced Multiple Myeloma: Pt Mel 140 ASCT # Mel 200 ASCT #1 Progression by IMWG Criteria CART19 Day Transplant Day CD19 negative PCs Clinical scr MRD neg (flow/sequencing)

32 Toxicity: CTL019 No significant acute infusional toxicity Tumor lysis syndrome (grade 3-4) Reversible and manageable Anticipated toxcities related to high dose melphalan B cell aplasia and hypogammaglobulinemia Supported with intravenous immunoglobulin (IVIG) No excessive or frequent infections Cytokine Release Syndrome (CRS) Monitor VS, ferritin level and CRP level

33 CD19-targeted CAR T cells: CRS Cytokine-release syndrome persistent high fevers, rigors, myalgias, hypotension, hypoxia very high IL6, lower levels of IFN-gamma, TNF can be associated with HLH/macrophage activation syndrome ferritin>50000, high CRP, altered mental status, seizures, DIC responds to steroids but lose CAR T cells tocilizumab (anti-il6 receptor mab) can abrogate CRS optimal timing, impact on efficacy not fully known Davila et al, Science Trans Med 2014; Porter et al, ASH 2013; #873

34 Temperature Response to Tocilizumab Temp Temp Tocilizumab , 6a 1, 12p 1, 6p 2. 12a 2. 6a 2. 12p 2, 6p 3, 12a 3. 6a 3. 12p 3. 6p 4, 12a 4. 6a 4. 12p 4. 6p 5, 12a 5. 6a 5. 12p 5. 6p 6, 12a 6. 6a

35 Ferritin Ferritin Response to Tocilizumab Tocilizumab: d Ferritin CRS, Pt

36 Conclusions: Myeloma CAR therapy Multiple promising targets: CD19, CD138, CD38, CD56, kappa, Lewis Y, CD44v6, CS1, BCMA Functional CAR T cells can be generated from MM patients CAR T and NK cells have in vitro and in vivo activity against MM Clinical trials underway Anecdotal prolonged responses but no robust efficacy data available yet Many questions remain about CAR design: optimal co-stimulatory domains optimal vector optimal dose and schedule need for chemotherapy Perhaps cocktails of multiple CARs or CARs + chemotherapy will be required for best outcomes

37 CARs for MM: selected data Target Antigen Rationale Results Concerns CD138 All plasma cells/epithelium Phase I with 2nd gen. T cell CAR (General Hospital of PLA, Beijing, NCT ) mucositis, down regulating CD138 CD38 All plasma cells/tcells, prostate, myeloid 2nd gen. T cell CAR active in vitro and xenografts for B-cell NHL, in vitro in MM3,4 Immune def /cytopenias CS1/SLAMF7 (CRACC, CD319) >95% plasma cells/t-cells, NK, DC 2 nd gen. CAR in NK92 or NKL human cell lines: In vitro killing of CS1+ MM lines and 1º MM cells Delayed growth of IM9 MM xenografts Immune def Kappa light chain 2/3rds plasma cells Phase I of 2 nd gen. T cell CAR in CLL,, NHL, 3 SD MM 1 Baylor light chain intracellular in myeloma cells?impact of high circulating light chains BCMA (B cell maturation antigen) All plasma cells/bcells anti-bcma-mmaf (GSK ) Induces apoptosis and ADCC against MM cells In vivo activity against MM xenografts4 NIH Phase I trial open CRS