Journal Article
. 2012 Apr; 72(12):2937-48.
doi: 10.1158/0008-5472.CAN-11-3368.

Gene immunotherapy of chronic lymphocytic leukemia: a phase I study of intranodally injected adenovirus expressing a chimeric CD154 molecule

Januario E Castro 1 Johanna Melo-Cardenas  Mauricio Urquiza  Juan S Barajas-Gamboa  Ramin S Pakbaz  Thomas J Kipps  
Affiliations
  • PMID: 22505652
  •     44 References
  •     19 citations

Abstract

New therapies for chronic lymphocytic leukemia (CLL) are needed, particularly those that can eradicate residual disease and elicit anti-CLL immune responses. CD40 ligation on CLL cells, which can be achieved using adenovirus encoding chimeric CD154 (Ad-ISF35), enhances their ability to function as antigen-presenting cells and increases their sensitivity to clearance by immune-effector mechanisms. In this study, we report the results of a first-in-man phase I trial of intranodal direct injection (IDI) of Ad-ISF35 in patients with CLL to evaluate toxicity, safety, and tolerability. Fifteen patients received a single IDI of 1 × 10(10) to 33 × 10(10) Ad-ISF35 viral particles (vp), with a defined maximum tolerated dose as 1 × 10(11) vp. Although the most common adverse events were transient grade 1 to 2 pain at the injection site and flu-like symptoms following IDI, some patients receiving the highest dose had transient, asymptomatic grade 3 to 4 hypophosphatemia, neutropenia, or transaminitis. Increased expression of death receptor, immune costimulatory molecules, and Ad-ISF35 vector DNA was detected in circulating CLL cells. Notably, we also observed preliminary clinical responses, including reductions in leukemia cell counts, lymphadenopathy, and splenomegaly. Six patients did not require additional therapy for more than 6 months, and three achieved a partial remission. In conclusion, Ad-ISF35 IDI was safely delivered in patients with CLLs and induced systemic biologic and clinical responses. These results provide the rationale for phase II studies in CLLs, lymphomas, and CD40-expressing solid tumors.

The antileukemia activity of a human anti-CD40 antagonist antibody, HCD122, on human chronic lymphocytic leukemia cells.
Mohammad Luqman, Sha Klabunde, +14 authors, Anas Younes.
Blood, 2008 May 24; 112(3). PMID: 18497318    Free PMC article.
Prevalence of hypophosphatemia in sepsis and infection: the role of cytokines.
V Barak, A Schwartz, +3 authors, Y Shoenfeld.
Am J Med, 1998 Apr 07; 104(1). PMID: 9528718
Intratumoral delivery of CD154 homolog (Ad-ISF35) induces tumor regression: analysis of vector biodistribution, persistence and gene expression.
J Melo-Cardenas, M Urquiza, T J Kipps, J E Castro.
Cancer Gene Ther, 2012 Mar 10; 19(5). PMID: 22402624    Free PMC article.
The roles of lymph node stromal cells in proliferation of lymphoid leukaemia cells.
H Tsuda, H Nishimura, T Sawada, K Takatsuki.
Br J Cancer, 1990 Mar 01; 61(3). PMID: 2328199    Free PMC article.
The effect of anti-CD40 ligand antibody on B cells in human systemic lupus erythematosus.
Weiqing Huang, Jayashree Sinha, +5 authors, Anne Davidson.
Arthritis Rheum, 2002 Jul 13; 46(6). PMID: 12115186
Immune recovery after fludarabine-cyclophosphamide-rituximab treatment in B-chronic lymphocytic leukemia: implication for maintenance immunotherapy.
L Ysebaert, E Gross, +5 authors, A Quillet-Mary.
Leukemia, 2010 May 14; 24(7). PMID: 20463751
Comparison of the effects of aging and IL-6 on the hepatic inflammatory response in two models of systemic injury: scald injury versus i.p. LPS administration.
Christian R Gomez, Vanessa Nomellini, +2 authors, Elizabeth J Kovacs.
Shock, 2008 Jul 19; 31(2). PMID: 18636046    Free PMC article.
The bone marrow microenvironment as a tumor sanctuary and contributor to drug resistance.
Mark B Meads, Lori A Hazlehurst, William S Dalton.
Clin Cancer Res, 2008 May 03; 14(9). PMID: 18451212
Highly Cited. Review.
Gene therapy of hematologic malignancies.
W G Wierda, T J Kipps.
Semin Oncol, 2000 Oct 26; 27(5). PMID: 11049018
Review.
Innate control of B cell responses.
Andrea Cerutti, Irene Puga, Montserrat Cols.
Trends Immunol, 2011 Mar 23; 32(5). PMID: 21419699    Free PMC article.
Review.
A phase I study of immune gene therapy for patients with CLL using a membrane-stable, humanized CD154.
W G Wierda, J E Castro, +6 authors, T J Kipps.
Leukemia, 2010 Oct 01; 24(11). PMID: 20882050    Free PMC article.
Fas-ligand (CD178) and TRAIL synergistically induce apoptosis of CD40-activated chronic lymphocytic leukemia B cells.
Frank Dicker, Arnon P Kater, Tetsuya Fukuda, Thomas J Kipps.
Blood, 2004 Sep 02; 105(8). PMID: 15339846
Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial.
M Hallek, K Fischer, +31 authors, German Chronic Lymphocytic Leukaemia Study Group.
Lancet, 2010 Oct 05; 376(9747). PMID: 20888994
Highly Cited.
The lymph node microenvironment promotes B-cell receptor signaling, NF-kappaB activation, and tumor proliferation in chronic lymphocytic leukemia.
Yair Herishanu, Patricia Pérez-Galán, +21 authors, Adrian Wiestner.
Blood, 2010 Oct 14; 117(2). PMID: 20940416    Free PMC article.
Highly Cited.
CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans.
Gregory L Beatty, Elena G Chiorean, +10 authors, Robert H Vonderheide.
Science, 2011 Mar 26; 331(6024). PMID: 21436454    Free PMC article.
Highly Cited.
Eradication of minimal residual disease in B-cell chronic lymphocytic leukemia after alemtuzumab therapy is associated with prolonged survival.
Paul Moreton, Ben Kennedy, +8 authors, Peter Hillmen.
J Clin Oncol, 2005 Mar 02; 23(13). PMID: 15738539
A phase I trial of intratumoral administration of recombinant oncolytic adenovirus overexpressing HSP70 in advanced solid tumor patients.
J-L Li, H-L Liu, +6 authors, D-T Chu.
Gene Ther, 2008 Dec 19; 16(3). PMID: 19092859
Antisera induced by infusions of autologous Ad-CD154-leukemia B cells identify ROR1 as an oncofetal antigen and receptor for Wnt5a.
Tetsuya Fukuda, Liguang Chen, +9 authors, Thomas J Kipps.
Proc Natl Acad Sci U S A, 2008 Feb 22; 105(8). PMID: 18287027    Free PMC article.
Highly Cited.
Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines.
Michael Hallek, Bruce D Cheson, +9 authors, International Workshop on Chronic Lymphocytic Leukemia.
Blood, 2008 Jan 25; 111(12). PMID: 18216293    Free PMC article.
Highly Cited.
National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment.
B D Cheson, J M Bennett, +4 authors, K R Rai.
Blood, 1996 Jun 15; 87(12). PMID: 8652811
Highly Cited.
A phase I trial of immunotherapy with intratumoral adenovirus-interferon-gamma (TG1041) in patients with malignant melanoma.
Alok A Khorana, J D Rosenblatt, +11 authors, K Kendra.
Cancer Gene Ther, 2003 Apr 08; 10(4). PMID: 12679797
Phase I study of recombinant human CD40 ligand in cancer patients.
R H Vonderheide, J P Dutcher, +10 authors, J G Gribben.
J Clin Oncol, 2001 Jul 04; 19(13). PMID: 11432896
Protection of CLL B cells by a follicular dendritic cell line is dependent on induction of Mcl-1.
Irene M Pedersen, Shinichi Kitada, +7 authors, John C Reed.
Blood, 2002 Aug 15; 100(5). PMID: 12176902
Clinical activity and immune modulation in cancer patients treated with CP-870,893, a novel CD40 agonist monoclonal antibody.
Robert H Vonderheide, Keith T Flaherty, +12 authors, Scott J Antonia.
J Clin Oncol, 2007 Mar 01; 25(7). PMID: 17327609
Highly Cited.
CD40 ligand deficiency presenting as unresponsive neutropenia.
F J Andrews, F Katz, +2 authors, A Finn.
Arch Dis Child, 1996 May 01; 74(5). PMID: 8669967    Free PMC article.
Evaluation of procalcitonin, neopterin, C-reactive protein, IL-6 and IL-8 as a diagnostic marker of infection in patients with febrile neutropenia.
Cristina Prat, Juan Manuel Sancho, +7 authors, Vicenc Ausina.
Leuk Lymphoma, 2008 Jul 29; 49(9). PMID: 18661397
Intratumoral injection of dendritic cells engineered to secrete interleukin-12 by recombinant adenovirus in patients with metastatic gastrointestinal carcinomas.
Guillermo Mazzolini, Carlos Alfaro, +17 authors, Ignacio Melero.
J Clin Oncol, 2004 Dec 16; 23(5). PMID: 15598979
Severe congenital neutropenia or hyper-IgM syndrome? A novel mutation of CD40 ligand in a patient with severe neutropenia.
Nima Rezaei, Asghar Aghamohammadi, +2 authors, Lennart Hammarstrom.
Int Arch Allergy Immunol, 2008 Jul 03; 147(3). PMID: 18594157
A short course of BG9588 (anti-CD40 ligand antibody) improves serologic activity and decreases hematuria in patients with proliferative lupus glomerulonephritis.
Dimitrios T Boumpas, Richard Furie, +5 authors, BG9588 Lupus Nephritis Trial Group.
Arthritis Rheum, 2003 Mar 13; 48(3). PMID: 12632425
Highly Cited.
Gene transfer of CD40-ligand induces autologous immune recognition of chronic lymphocytic leukemia B cells.
K Kato, M J Cantwell, S Sharma, T J Kipps.
J Clin Invest, 1998 Apr 16; 101(5). PMID: 9486984    Free PMC article.
Successful management of neutropenia in a patient with CD40 ligand deficiency by immunoglobulin replacement therapy.
Lida Atarod, Asghar Aghamohammadi, +6 authors, Miyawaki Miyawaki.
Iran J Allergy Asthma Immunol, 2007 Feb 17; 6(1). PMID: 17303928
Immunogenetic therapy for B-cell malignancies.
T J Kipps, P Chu, W G Wierda.
Semin Oncol, 2001 Feb 28; 27(6 Suppl 12). PMID: 11225994
Review.
Adenoviral transduction of tumor cells induces apoptosis in co-cultured T lymphocytes.
C Scholz, L Stärck, +3 authors, P T Daniel.
Gene Ther, 2002 Oct 16; 9(21). PMID: 12378406
Diverse marrow stromal cells protect CLL cells from spontaneous and drug-induced apoptosis: development of a reliable and reproducible system to assess stromal cell adhesion-mediated drug resistance.
Antonina V Kurtova, Kumudha Balakrishnan, +13 authors, Jan A Burger.
Blood, 2009 Sep 19; 114(20). PMID: 19762485    Free PMC article.
Highly Cited.
Improved vaccination response during ranitidine treatment, and increased plasma histamine concentrations, in patients with B cell chronic lymphocytic leukemia.
J Jurlander, P de Nully Brown, +7 authors, H J Nielsen.
Leukemia, 1995 Nov 01; 9(11). PMID: 7475282
ZAP-70 compared with immunoglobulin heavy-chain gene mutation status as a predictor of disease progression in chronic lymphocytic leukemia.
Laura Z Rassenti, Lang Huynh, +11 authors, Thomas J Kipps.
N Engl J Med, 2004 Aug 27; 351(9). PMID: 15329427
Highly Cited.
Autoimmune disease induced by dendritic cell immunization against leukemia.
M A Roskrow, D Dilloo, +3 authors, M K Brenner.
Leuk Res, 1999 Jun 22; 23(6). PMID: 10374848
Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia.
Constantine S Tam, Susan O'Brien, +7 authors, Michael J Keating.
Blood, 2008 Apr 16; 112(4). PMID: 18411418    Free PMC article.
Highly Cited.
CD40-activated B-cell chronic lymphocytic leukemia cells for tumor immunotherapy: stimulation of allogeneic versus autologous T cells generates different types of effector cells.
R Buhmann, A Nolte, +2 authors, M Hallek.
Blood, 1999 Mar 09; 93(6). PMID: 10068672
Biology and clinical applications of CD40 in cancer treatment.
Ester Fonsatti, Michele Maio, Maresa Altomonte, Peter Hersey.
Semin Oncol, 2010 Nov 16; 37(5). PMID: 21074067
Review.
Activated T cells induce expression of B7/BB1 on normal or leukemic B cells through a CD40-dependent signal.
E A Ranheim, T J Kipps.
J Exp Med, 1993 Apr 01; 177(4). PMID: 7681471    Free PMC article.
Highly Cited.
Serum levels of IL-1 beta, sIL-2R, IL-6, IL-8, and TNF-alpha in febrile children with cancer and neutropenia.
M Soker, L Colpan, +2 authors, K Haspolat.
Med Oncol, 2002 Jan 10; 18(1). PMID: 11778970
Chronic lymphocytic leukemia T cells show impaired immunological synapse formation that can be reversed with an immunomodulating drug.
Alan G Ramsay, Amy J Johnson, +5 authors, John G Gribben.
J Clin Invest, 2008 Jun 14; 118(7). PMID: 18551193    Free PMC article.
Highly Cited.
CD40-ligand (CD154) gene therapy for chronic lymphocytic leukemia.
W G Wierda, M J Cantwell, +3 authors, T J Kipps.
Blood, 2000 Oct 26; 96(9). PMID: 11049967
Trial watch: DNA vaccines for cancer therapy.
Laura Senovilla, Erika Vacchelli, +6 authors, Lorenzo Galluzzi.
Oncoimmunology, 2013 Jun 05; 2(4). PMID: 23734328    Free PMC article.
Immunotherapy for chronic lymphocytic leukemia in the era of BTK inhibitors.
M A Kharfan-Dabaja, W G Wierda, L J N Cooper.
Leukemia, 2013 Oct 26; 28(3). PMID: 24157582
Review.
Potent fluorinated agelastatin analogues for chronic lymphocytic leukemia: design, synthesis, and pharmacokinetic studies.
E Paige Stout, Michael Y Choi, Januario E Castro, Tadeusz F Molinski.
J Med Chem, 2014 Mar 29; 57(12). PMID: 24673739    Free PMC article.
Trial Watch: DNA vaccines for cancer therapy.
Jonathan Pol, Norma Bloy, +7 authors, Lorenzo Galluzzi.
Oncoimmunology, 2014 May 07; 3(1). PMID: 24800178    Free PMC article.
Review.
Intratumoral injection of Ad-ISF35 (Chimeric CD154) breaks tolerance and induces lymphoma tumor regression.
Mauricio Urquiza, Johanna Melo-Cardenas, +2 authors, Januario E Castro.
Hum Gene Ther, 2014 Nov 11; 26(1). PMID: 25382101    Free PMC article.
Nanotechnology for cancer treatment.
William H Gmeiner, Supratim Ghosh.
Nanotechnol Rev, 2015 Jun 18; 3(2). PMID: 26082884    Free PMC article.
Going viral: a review of replication-selective oncolytic adenoviruses.
Christopher Larson, Bryan Oronsky, +4 authors, Tony R Reid.
Oncotarget, 2015 Aug 19; 6(24). PMID: 26280277    Free PMC article.
Review.
Immunostimulatory Gene Therapy Using Oncolytic Viruses as Vehicles.
Angelica Loskog.
Viruses, 2015 Nov 13; 7(11). PMID: 26561829    Free PMC article.
Review.
GIFT4 fusokine converts leukemic B cells into immune helper cells.
Jiusheng Deng, Andrea Pennati, +5 authors, Jacques Galipeau.
J Transl Med, 2016 Apr 28; 14(1). PMID: 27118475    Free PMC article.
Emerging nanotechnologies for cancer immunotherapy.
Sourabh Shukla, Nicole F Steinmetz.
Exp Biol Med (Maywood), 2016 May 18; 241(10). PMID: 27190253    Free PMC article.
Review.
Immune-Complexed Adenovirus Induce AIM2-Mediated Pyroptosis in Human Dendritic Cells.
Karsten Eichholz, Thierry Bru, +7 authors, Eric J Kremer.
PLoS Pathog, 2016 Sep 17; 12(9). PMID: 27636895    Free PMC article.
Intratumoral CD40 activation and checkpoint blockade induces T cell-mediated eradication of melanoma in the brain.
Manisha Singh, Christina Vianden, +15 authors, Willem W Overwijk.
Nat Commun, 2017 Nov 14; 8(1). PMID: 29129918    Free PMC article.
Gamma Delta T Cell Therapy for Cancer: It Is Good to be Local.
C David Pauza, Mei-Ling Liou, +4 authors, Haishan Li.
Front Immunol, 2018 Jun 26; 9. PMID: 29937769    Free PMC article.
Review.
VLPs Derived from the CCMV Plant Virus Can Directly Transfect and Deliver Heterologous Genes for Translation into Mammalian Cells.
María V Villagrana-Escareño, Elizabeth Reynaga-Hernández, +4 authors, Jaime Ruíz-García.
Biomed Res Int, 2019 Nov 30; 2019. PMID: 31781617    Free PMC article.
CD40 Ligand-Modified Chimeric Antigen Receptor T Cells Enhance Antitumor Function by Eliciting an Endogenous Antitumor Response.
Nicholas F Kuhn, Terence J Purdon, +4 authors, Renier J Brentjens.
Cancer Cell, 2019 Mar 20; 35(3). PMID: 30889381    Free PMC article.
Highly Cited.
New emerging targets in cancer immunotherapy: the role of Cluster of Differentiation 40 (CD40/TNFR5).
Manuel Piechutta, Anna Sophie Berghoff.
ESMO Open, 2019 Jul 06; 4(Suppl 3). PMID: 31275618    Free PMC article.
Review.
Programming CAR T cells to enhance anti-tumor efficacy through remodeling of the immune system.
Xiaohui Wang, Zhiqiang Wu, +3 authors, Weidong Han.
Front Med, 2020 Aug 15; 14(6). PMID: 32794014
Review.
Hematopoietic versus Solid Cancers and T Cell Dysfunction: Looking for Similarities and Distinctions.
Chiara Montironi, Cristina Muñoz-Pinedo, Eric Eldering.
Cancers (Basel), 2021 Jan 21; 13(2). PMID: 33466674    Free PMC article.
Review.
Research progress on dendritic cell vaccines in cancer immunotherapy.
Jifeng Yu, Hao Sun, +2 authors, Zhongxing Jiang.
Exp Hematol Oncol, 2022 Jan 26; 11(1). PMID: 35074008    Free PMC article.
Review.