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22-07-2017 | Lymphoma | Article

An Update on the Use of Immunotherapy in the Treatment of Lymphoma

Journal: Current Hematologic Malignancy Reports

Authors: Thomas U. Marron, Matko Kalac, Joshua Brody

Publisher: Springer US

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Abstract

Purpose of Review

Throughout the field of oncology, immunotherapy is moving further towards the first-line setting, and there is encouraging data for the use of these novel therapies in the management of lymphomas, utilizing treatments approved for both solid and hematologic malignancies. Herein, we review promising advances in this rapidly moving field from the past year.

Recent Findings

In the last year, we have seen promising clinical data on engineered antibody therapies for the treatment of lymphomas, as well as further optimization of engineered antibody fragments fused onto linkers or chimeric T cell receptors, both of the modalities capable of transforming non-specific T cells into tumor-specific, serial killer cells.

Summary

Here we will review the promising data on these advances in antibody-based therapies, as well as some of the immunomodulators and checkpoint-blocking therapies that shown to have promising results in the treatment of lymphomas within the past year.
Literature
1.
Le Gouill S, Thieblemont C, Oberic L, Moreau A, Bouabdallah K, Gyan E, et al. Rituximab maintenance after autologous stem cell transplantation prolongs survival in younger patients with mantle cell lymphoma: final results of the randomized phase 3 LyMa Trial of the Lysa/Goelams Group. Blood. 2016;128(22):145.
2.
Golay J, Da Roit F, Bologna L, Ferrara C, Leusen JH, Rambaldi A, et al. Glycoengineered CD20 antibody obinutuzumab activates neutrophils and mediates phagocytosis through CD16B more efficiently than rituximab. Blood. 2013;122(20):3482–91.CrossRefPubMed
3.
Terszowski G, Klein C, Stern M. KIR/HLA interactions negatively affect rituximab—but not GA101 (obinutuzumab)-induced antibody-dependent cellular cytotoxicity. J Immunol. 2014;192(12):5618–24.CrossRefPubMed
4.
Vitolo U, Trněný M, Belada D, Carella AM, Chua N, Abrisqueta P, et al. Obinutuzumab or rituximab plus CHOP in patients with previously untreated diffuse large B-cell lymphoma: final results from an open-label, randomized phase 3 study (GOYA). Blood. 2016;128(22):470.
5.
•• Goede V, Fischer K, Busch R, Engelke A, Eichhorst B, Wendtner CM, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014;370(12):1101–10. The randomized phase 3, CLL11 trial substantiated nearly 20 years of research since the 1997 approval of rituximab to result in the first clinically significant improvement in anti-CD20 antibody therapy, demonstrating a PFS improvement with obinutuzumab versus rituximab (and an OS improvement versus no antibody). Later follow-up demonstrated the OS benefit versus rituximab coming closer towards significance (0.11 in this study, 0.09 in subsequent follow-up). Thus study should inspire continued research into optimization of antibody effector function across different molecular targets, lymphoid and otherwise. CrossRefPubMed
6.
Marcus RE, Davies AJ, Ando K, Klapper W, Opat S, Owen CJ, et al. Obinutuzumab-based induction and maintenance prolongs progression-free survival (PFS) in patients with previously untreated follicular lymphoma: primary results of the randomized phase 3 GALLIUM study. Blood. 2016;128(22):6.
7.
Eichenauer DA, Goergen H, Plutschow A, Wongso D, Behringer K, Kreissl S, et al. Ofatumumab in relapsed nodular lymphocyte-predominant Hodgkin lymphoma: results of a phase II study from the German Hodgkin study group. Leukemia. 2016;30(6):1425–7.CrossRefPubMed
8.
Osterborg A, Dyer MJ, Bunjes D, Pangalis GA, Bastion Y, Catovsky D, et al. Phase II multicenter study of human CD52 antibody in previously treated chronic lymphocytic leukemia. European study group of CAMPATH-1H treatment in chronic lymphocytic leukemia. J Clin Oncol. 1997;15(4):1567–74.CrossRefPubMed
9.
Horton HM, Bernett MJ, Pong E, Peipp M, Karki S, Chu SY, et al. Potent in vitro and in vivo activity of an Fc-engineered anti-CD19 monoclonal antibody against lymphoma and leukemia. Cancer Res. 2008;68(19):8049–57.CrossRefPubMed
10.
Woyach JA, Awan F, Flinn IW, Berdeja JG, Wiley E, Mansoor S, et al. A phase 1 trial of the Fc-engineered CD19 antibody XmAb5574 (MOR00208) demonstrates safety and preliminary efficacy in relapsed CLL. Blood. 2014;124(24):3553–60.CrossRefPubMedPubMedCentral
11.
Jurczak W, Zinzani PL, Gaidano G, Goy A, Provencio M, Nagy Z, et al. Single-agent MOR208 in relapsed or refractory (R-R) non-Hodgkin's lymphoma (NHL): results from diffuse large B-cell lymphoma (DLBCL) and indolent NHL subgroups of a phase IIa study. Blood. 2016;128(22):623.
12.
Woyach JA, Ruppert AS, Awan FT, Jones J, Andritsos LA, Waymer S, et al. Updated results from a phase II study of the fc engineered CD19 antibody MOR208 in combination with lenalidomide for patients with chronic lymphocytic leukemia (CLL) and Richter’s transformation or Ibrutinib for patients with Ibrutinib-resistant clones. Blood. 2016;128(22):4386.
13.
Budde LE, Halwani A, Yasenchak CA, Farber CM, Burke JM, Fayad LE, et al. Results of an ongoing phase 2 study of brentuximab vedotin with Rchp as frontline therapy in patients with high-intermediate/high-risk diffuse large B cell lymphoma (DLBCL). Blood. 2016;128(22):104.
14.
Kim YH, Whittaker S, Horwitz SM, Duvic M, Dummer R, Scarisbrick JJ, et al. Brentuximab vedotin demonstrates significantly superior clinical outcomes in patients with CD30-expressing cutaneous T cell lymphoma versus physician’s choice (methotrexate or bexarotene): the phase 3 Alcanza study. Blood. 2016;128(22):182.
15.
Hari P, Raj RV, Olteanu H. Targeting CD38 in refractory extranodal natural killer cell-T-cell lymphoma. N Engl J Med. 2016;375(15):1501–2.CrossRefPubMed
16.
• Phillips T, Brunvand M, Chen A, Press O, Essell J, Chiappella A, et al. Polatuzumab vedotin combined with obinutuzumab for patients with relapsed or refractory non-hodgkin lymphoma: preliminary safety and clinical activity of a phase Ib/II study. Blood. 2016;128(22):622. This single patient case report is acknowledged in a high impact journal because of the slow therapeutic advancement in T cell (as compared to B cell) NHL and paucity of ongoing clinical trials for novel agents in these diseases. Subsequent to this publication, a Phase 2 trial assessing the agent in relapsed NK/T lymphoma has been initiated (NCT02927925). Of note, a proportion of both AITL and PTCL-NOS also express moderate to high levels of CD38.
17.
Phillips A, Fields P, Hermine O, Ramos JC, Beltran BE, Pereira J, et al. A prospective, multicenter, randomized study of anti-CCR4 monoclonal antibody mogamulizumab versus investigator’s choice in the treatment of patients with relapsed/refractory adult T-cell leukemia-lymphoma: overall response rate, progression-free survival, and overall survival. Blood. 2016;128(22):4159.
18.
Bargou R, Leo E, Zugmaier G, Klinger M, Goebeler M, Knop S, et al. Tumor regression in cancer patients by very low doses of a T cell-engaging antibody. Science. 2008;321(5891):974–7.CrossRefPubMed
19.
Baeuerle PA, Reinhardt C. Bispecific T-cell engaging antibodies for cancer therapy. Cancer Res. 2009;69(12):4941–4.CrossRefPubMed
20.
Goebeler ME, Knop S, Viardot A, Kufer P, Topp MS, Einsele H, et al. Bispecific T-cell engager (BiTE) antibody construct blinatumomab for the treatment of patients with relapsed/refractory non-Hodgkin lymphoma: final results from a phase I study. J Clin Oncol. 2016;34(10):1104–11.CrossRefPubMed
21.
• Viardot A, Goebeler ME, Hess G, Neumann S, Pfreundschuh M, Adrian N, et al. Phase 2 study of the bispecific T-cell engager (BiTE) antibody blinatumomab in relapsed/refractory diffuse large B-cell lymphoma. Blood. 2016;127(11):1410–6. The largest study to date assessing the efficacy of bi-specific antibody therapy in a disease other than ALL, demonstrating 43%ORR and 19%CR, comparing favorably with other novel agents in this group of relapsed DLBCL patients. Clinical trials combining bi-specifics with checkpoint blockade are ongoing. CrossRefPubMedPubMedCentral
22.
Topp MS, Gokbuget N, Stein AS, Zugmaier G, O’Brien S, Bargou RC, et al. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol. 2015;16(1):57–66.CrossRefPubMed
23.
Smith EJ, Olson K, Haber LJ, Varghese B, Duramad P, Tustian AD, et al. A novel, native-format bispecific antibody triggering T-cell killing of B-cells is robustly active in mouse tumor models and cynomolgus monkeys. Sci Rep. 2015;5:17943.CrossRefPubMedPubMedCentral
24.
Bannerji R, Brown JR, Advani RH, Arnason J, O’Brien SM, Allan JN, et al. Phase 1 study of REGN1979, an anti-CD20 x anti-CD3 Bispecific monoclonal antibody, in patients with CD20+ B-cell malignancies previously treated with CD20-directed antibody therapy. Blood. 2016;128(22):621.
25.
Bashey A, Medina B, Corringham S, Pasek M, Carrier E, Vrooman L, et al. CTLA4 blockade with ipilimumab to treat relapse of malignancy after allogeneic hematopoietic cell transplantation. Blood. 2009;113(7):1581–8.CrossRefPubMedPubMedCentral
26.
Davids MS, Kim HT, Bachireddy P, Costello C, Liguori R, Savell A, et al. Ipilimumab for patients with relapse after allogeneic transplantation. N Engl J Med. 2016;375(2):143–53.CrossRefPubMedPubMedCentral
27.
Khouri IF, Curbelo IF, Turturro F, Milton DR, Kim RA, Jabbour EJ, et al. Lenalidomide with ipilimumab for lymphoid malignancies after allogeneic or autologous stem cell transplantation (SCT). Blood. 2016;128(22):1164.
28.
Berger R, Rotem-Yehudar R, Slama G, Landes S, Kneller A, Leiba M, et al. Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies. Clin Cancer Res. 2008;14(10):3044–51.CrossRefPubMed
29.
Westin JR, Chu F, Zhang M, Fayad LE, Kwak LW, Fowler N, et al. Safety and activity of PD1 blockade by pidilizumab in combination with rituximab in patients with relapsed follicular lymphoma: a single group, open-label, phase 2 trial. Lancet Oncol. 2014;15(1):69–77.CrossRefPubMed
30.
•• Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. 2015;372(4):311–9. This seminal study both set a new standard of care for salvage therapy in Hodgkin’s Lymphoma -resulting in the agent’s FDA approval- and demonstrated amongst the highest response rates for checkpoint blockade immunotherapy in any malignancy. CrossRefPubMed
31.
Armand P, Shipp MA, Ribrag V, Michot J-M, Zinzani PL, Kuruvilla J, et al. Programmed death-1 blockade with pembrolizumab in patients with classical Hodgkin lymphoma after brentuximab vedotin failure. J Clin Oncol. 2016;34(31):3733-9. doi:10.​1200/​jco.​2016.​67.​3467.
32.
Diefenbach CS, Hong F, David KA, Cohen J, Robertson M, Advani R, et al. Title: a phase I study with an expansion cohort of the combination of ipilimumab and nivolumab and brentuximab vedotin in patients with relapsed/refractory Hodgkin lymphoma: a trial of the ECOG-ACRIN Cancer Research Group (E4412 arms D and E). Blood. 2016;128(22):1106.
33.
Roemer MG, Advani RH, Ligon AH, Natkunam Y, Redd RA, Homer H, et al. PD-L1 and PD-L2 genetic alterations define classical Hodgkin lymphoma and predict outcome. J Clin Oncol. 2016;34(23):2690–7.CrossRefPubMedPubMedCentral
34.
Chapuy B, Roemer MGM, Stewart C, Tan Y, Abo RP, Zhang L, et al. Targetable genetic features of primary testicular and primary central nervous system lymphomas. Blood. 2016;127(7):869–81.CrossRefPubMedPubMedCentral
35.
Zinzani PL, Ribrag V, Moskowitz CH, Michot J-M, Kuruvilla J, Balakumaran A, et al. Phase 1b study of pembrolizumab in patients with relapsed/refractory primary mediastinal large b-cell lymphoma: results from the ongoing Keynote-013 trial. Blood. 2016;128(22):619.
36.
Khodadoust M, Rook AH, Porcu P, Foss FM, Moskowitz AJ, Shustov AR, et al. Pembrolizumab for treatment of relapsed/refractory mycosis fungoides and sezary syndrome: clinical efficacy in a citn multicenter phase 2 study. Blood. 2016;128(22):181.
37.
Dann EJ, Daugherty CK, Larson RA. Allogeneic bone marrow transplantation for relapsed and refractory Hodgkin’s disease and non-Hodgkin’s lymphoma. Bone Marrow Transplant. 1997;20(5):369–74.CrossRefPubMed
38.
• Heslop HE, Slobod KS, Pule MA, Hale GA, Rousseau A, Smith CA, et al. Long-term outcome of EBV-specific T-cell infusions to prevent or treat EBV-related lymphoproliferative disease in transplant recipients. Blood. 2010;115(5):925–35. This study is the first to bring one of the newer, ‘targeted’ agents approved for MCL salvage therapy into an up-front, chemo-free regimen, with impressive response rates even comparing favorably with recent up-front MCL trials of R-Bendamustine or R-CHOP (e.g. BRIGHT study). The high frequency of ATM and p53 mutations in MCL suggests that immunotherapy-based therapies might avoid selection of -or induction of- aggressive, chemo-resistant sub-clones. CrossRefPubMedPubMedCentral
39.
Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011;365(8):725–33.CrossRefPubMedPubMedCentral
40.
Jensen MC, Popplewell L, Cooper LJ, DiGiusto D, Kalos M, Ostberg JR, et al. Antitransgene rejection responses contribute to attenuated persistence of adoptively transferred CD20/CD19-specific chimeric antigen receptor redirected T cells in humans. Biol Blood Marrow Transplant. 2010;16(9):1245–56.CrossRefPubMedPubMedCentral
41.
Savoldo B, Ramos CA, Liu E, Mims MP, Keating MJ, Carrum G, et al. CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. J Clin Invest. 2011;121(5):1822–6.CrossRefPubMedPubMedCentral
42.
Kochenderfer JN, Wilson WH, Janik JE, Dudley ME, Stetler-Stevenson M, Feldman SA, et al. Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. Blood. 2010;116(20):4099–102.CrossRefPubMedPubMedCentral
43.
Kochenderfer JN, Yu Z, Frasheri D, Restifo NP, Rosenberg SA. Adoptive transfer of syngeneic T cells transduced with a chimeric antigen receptor that recognizes murine CD19 can eradicate lymphoma and normal B cells. Blood. 2010;116(19):3875–86.CrossRefPubMedPubMedCentral
44.
Kochenderfer JN, Dudley ME, Kassim SH, Somerville RP, Carpenter RO, Stetler-Stevenson M, et al. Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J Clin Oncol. 2015;33(6):540–9.CrossRefPubMed
45.
Schuster SJ, Svoboda J, Nasta SD, Chong EA, Winchell N, Landsburg DJ, et al. Treatment with chimeric antigen receptor modified T cells directed against CD19 (CTL019) results in durable remissions in patients with relapsed or refractory diffuse large B cell lymphomas of germinal center and non-germinal center origin, “double hit” diffuse large B cell lymphomas, and transformed follicular to diffuse large B cell lymphomas. Blood. 2016;128(22):3026.
46.
Locke FL, Neelapu SS, Bartlett NL, Lekakis LJ, Miklos D, Jacobson CA, et al. Abstract CT019: primary results from ZUMA-1: a pivotal trial of axicabtagene ciloleucel (axicel; KTE-C19) in patients with refractory aggressive non-Hodgkin lymphoma (NHL). Cancer Research. 2017;77(13 Supplement): CT019-CT. doi:10.​1158/​1538-7445.​am2017-ct019.
47.
Crump M, Neelapu SS, Farooq U, Neste EVD, Kuruvilla J, Ahmed MA, et al. Outcomes in refractory aggressive diffuse large b-cell lymphoma (DLBCL): Results from the international SCHOLAR-1 study. J Clin Oncol. 2016;34(15_suppl):7516-. doi:10.​1200/​JCO.​2016.​34.​15_​suppl.​7516.
48.
Gomes da Silva D, Mukherjee M, Srinivasan M, Dakhova O, Liu H, Grilley B, et al. Direct comparison of in vivo fate of second and third-generation CD19-specific chimeric antigen receptor (CAR)-T cells in patients with B-cell lymphoma: reversal of toxicity from tonic signaling. Blood. 2016;128(22):1851.
49.
Porter DL, Hwang WT, Frey NV, Lacey SF, Shaw PA, Loren AW, et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med. 2015;7(303):303ra139.CrossRefPubMed
50.
Brudno JN, Shi V, Stroncek D, Pittaluga S, Kanakry JA, Curtis LM, et al. T cells expressing a novel fully-human anti-CD19 chimeric antigen receptor induce remissions of advanced lymphoma in a first-in-humans clinical trial. Blood. 2016;128(22):999.
51.
Turtle CJ, Hanafi LA, Berger C, Gooley TA, Cherian S, Hudecek M, et al. CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J Clin Invest. 2016;126(6):2123–38.CrossRefPubMedPubMedCentral
52.
Sotillo E, Barrett DM, Black KL, Bagashev A, Oldridge D, Wu G, et al. Convergence of acquired mutations and alternative splicing of CD19 enables resistance to CART-19 immunotherapy. Cancer Discov. 2015;5(12):1282–95.CrossRefPubMedPubMedCentral
53.
Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371(16):1507–17.CrossRefPubMedPubMedCentral
54.
Shah NN, Stetler-Stevenson M, Yuan CM, Shalabi H, Yates B, Delbrook C, et al. Minimal residual disease negative complete remissions following anti-CD22 chimeric antigen receptor (CAR) in children and young adults with relapsed/refractory acute lymphoblastic leukemia (ALL). Blood. 2016;128(22):650.
55.
•• Cherkassky L, Morello A, Villena-Vargas J, Feng Y, Dimitrov DS, Jones DR, et al. Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition. J Clin Invest. 2016;126(8):3130–44. This abstract describes the seminal dataset from the ZUMA-1 study which was used for the registration of ‘axicel’ an immunotherapy milestone, apparently the first FDA-approved CAR-T product and an important model and proof-of-principle for subsequent approvals. CrossRefPubMedPubMedCentral
56.
Chong EA, Melenhorst JJ, Lacey SF, Ambrose DE, Gonzalez V, Levine BL, et al. PD-1 blockade modulates chimeric antigen receptor (CAR)–modified T cells: refueling the CAR. Blood. 2017;129(8):1039–41.CrossRefPubMedPubMedCentral
57.
Brody JD, Ai WZ, Czerwinski DK, Torchia JA, Levy M, Advani RH, et al. In situ vaccination with a TLR9 agonist induces systemic lymphoma regression: a phase I/II study. J Clin Oncol. 2010;28(28):4324–32.CrossRefPubMedPubMedCentral
58.
Kim YH, Gratzinger D, Harrison C, Brody JD, Czerwinski DK, Ai WZ, et al. In situ vaccination against mycosis fungoides by intratumoral injection of a TLR9 agonist combined with radiation: a phase 1/2 study. Blood. 2012;119(2):355–63.CrossRefPubMedPubMedCentral
59.
Salem ML, Kadima AN, Cole DJ, Gillanders WE. Defining the antigen-specific T-cell response to vaccination and poly(I:C)/TLR3 signaling: evidence of enhanced primary and memory CD8 T-cell responses and antitumor immunity. J Immunother. 2005;28(3):220–8.CrossRefPubMed
60.
Salazar AM, Erlich RB, Mark A, Bhardwaj N, Herberman RB. Therapeutic in situ autovaccination against solid cancers with intratumoral poly-ICLC: case report, hypothesis, and clinical trial. Cancer Immunol Res. 2014;2(8):720–4.CrossRefPubMed
61.
Bhardwaj N, Merad M, Kim-Schulze S, Crowley B, Davis T, Salazar A, et al. Converting tumors into vaccine manufacturing factories: DC recruitment, activation and clinical responses with a flt3L-primed in situ vaccine for low-grade lymphoma [nct01976585]. J Immunother Cancer. 2014;2(Suppl 3):45.CrossRef
62.
Marron T, Bhardwaj N, Crowley E, Keler T, Davis TA, Brody J. Turning a tumor into a vaccine factory: in situ vaccination for low-grade lymphoma. Blood. 2014;124(21):5473-5473.
63.
Flowers C, Isufi I, Herrera A, Okada C, Cull E, Kis B, et al. Intratumoral G100 induces systemic immune responses and abscopal tumor regression in patients with follicular lymphoma [abstract]. J Clin Oncol Off J Am Soc Clin Oncol. 2017; Abstract 7537.