Human granulocyte–macrophage colony-stimulating factor DNA cationic-lipid complexed autologous tumour cell vaccination in the treatment of canine B-cell multicentric lymphoma

Turek, Michelle; Thamm, Douglas H.; Mitzey, Ann M.; Kurzman, Ilene D.; Huelsmeyer, M. K.; Dubielzig, Richard R.; Vail, David M.

doi:10.1111/j.1476-5829.2007.00128.x

Cited by 28 publications

(21 citation statements)

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“…Therapeutic cancer vaccines target TAAs to induce an active immune response, and 4 earlyphase clinical trials in dogs with B-cell lymphoma have provided a strong rationale for this approach (17)(18)(19)(20). Nevertheless, immunotherapeutic strategies have to face an important obstacle: the ability of tumor cells to evade the immune attack (23).…”

Section: Discussionmentioning

confidence: 99%

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Randomized, Placebo-Controlled, Double-Blinded Chemoimmunotherapy Clinical Trial in a Pet Dog Model of Diffuse Large B-cell Lymphoma

Marconato

Frayssinet

Rouquet

et al. 2014

Clinical Cancer Research

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Purpose: Active immunotherapy is a promising antitumoral strategy; however its use in combination with chemotherapy in dogs with large B-cell lymphoma (DLBCL) remains largely untested. Heat shock proteins (HSP) bind the small peptides they chaperone (HSPPC), allowing for immunization of the host against a large repertoire of tumor-associated antigens. Hydroxylapatite vehicles HSPPCs and acts as an immunologic adjuvant. The aim of this study was to show that an autologous vaccine with hydroxylapatite and tumor-derived HSPPCs is safe and therapeutically effective in dogs with DLBCL.Experimental Design: Nineteen dogs with naturally occurring DLBCL were entered into a prospective randomized placebo-controlled double-blinded trial of HSPPCs-hydroxylapatite plus chemotherapy versus chemotherapy alone. Endpoints included time to progression (TTP), lymphoma-specific survival (LSS), and incidence of toxicoses.Results: Median first TTP after randomization to the vaccine arm was 304 days versus 41 days for the control arm (P ¼ 0.0004). There was also a statistically significant difference in duration of second remission between the two groups (P ¼ 0.02). Median LSS was 505 days for the vaccinated dogs versus 159 days for the unvaccinated dogs (P ¼ 0.0018). Six vaccinated dogs achieved molecular remission, as shown by clonal immunoglobulin H (IgH) rearrangement. Toxicoses were comparable between the two treatment arms.Conclusions: The results of this trial demonstrate that the autologous vaccine tested here is safe and efficacious in prolonging TTP and LSS in dogs with DLBCL when used in combination with dose-intense chemotherapy. On the basis of these results, additional evaluation of this novel therapeutic strategy is warranted in human DLBCL. Clin Cancer Res; 20(3); 668-77. Ó2013 AACR.

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Section: Discussionmentioning

confidence: 99%

“…Later, an autologous tumor cell vaccine administered to dogs with B-cell lymphoma following chemotherapy did not improve the outcome when compared with placebomatched dogs (18).…”

Section: Introductionmentioning

confidence: 99%

Randomized, Placebo-Controlled, Double-Blinded Chemoimmunotherapy Clinical Trial in a Pet Dog Model of Diffuse Large B-cell Lymphoma

Marconato

Frayssinet

Rouquet

et al. 2014

Clinical Cancer Research

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“…Canine non-Hodgkin's lymphoma has proven to be a relevant model for preclinical evaluation of new therapeutics for both initial induction and rescue of drug-resistant relapse (8)(9)(10)(11)(12)(13)(14). Evaluation of novel therapeutic approaches in dogs with spontaneous cancer offers potential benefit to canine patients and a rapid assessment of therapeutic index.…”

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confidence: 99%

Assessment of GS-9219 in a Pet Dog Model of Non-Hodgkin's Lymphoma

Vail

Thamm

Reiser

et al. 2009

Clinical Cancer Research

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Purpose: To assess, in dogs with naturally occurring non-Hodgkin's lymphoma, pharmacokinetics, safety, and activity of GS-9219, a prodrug of the nucleotide analogue 9-(2-phosphonylmethoxyethyl) guanine (PMEG), which delivers PMEG and its phosphorylated metabolites to lymphoid cells with preferential cytotoxicity in cells with a high proliferation index such as lymphoid malignancies. Experimental Design: To generate proof-of-concept, a phase I/II trial was conducted in pet dogs (n = 38) with naturally occurring non-Hodgkin's lymphoma using different dose schedules of GS-9219. A subset of dogs was further evaluated with 3′-deoxy-3′-18 F-fluorothymidine positron emission tomography/computed tomography imaging before and after treatment. Results: The prodrug had a short plasma half-life but yielded high and prolonged intracellular levels of the cytotoxic metabolite PMEG diphosphate in peripheral blood mononuclear cells in the absence of detectable plasma PMEG. Dose-limiting toxicities were generally manageable and reversible and included dermatopathy, neutropenia, and gastrointestinal signs. Antitumor responses were observed in 79% of dogs and occurred in previously untreated dogs and dogs with chemotherapy-refractory non-Hodgkin's lymphoma. The median remission durations observed compare favorably with other monotherapies in dogs with non-Hodgkin's lymphoma. High 3′-deoxy-3′-18 F-fluorothymidine uptake noted in lymphoid tissues before treatment decreased significantly after treatment (P = 0.016). Conclusions: GS-9219 was generally well tolerated and showed significant activity against spontaneous non-Hodgkin's lymphoma as modeled in pet dogs and, as such, supports clinical evaluation in humans.Non-Hodgkin's lymphoma is the fifth leading cause of cancer deaths and the second fastest-growing form of cancer in the United States. In the latest compilation of Surveillance, Epidemiology and End Results reports, the incidence and death rate for non-Hodgkin's lymphoma continue to increase despite an overall decrease in overall cancer incidence (1). Therefore, there is still a major unmet medical need in non-Hodgkin's lymphoma patients for novel agents with improved efficacy compared with existing treatment modalities, especially in patients who have failed frontline therapy.The acyclic nucleotide phosphonate 9-(2-phosphonylmethoxyethyl) guanine (PMEG) forms an active phosphorylated metabolite, PMEG diphosphate, in cells and causes cytotoxicity in dividing cells due to potent inhibition of the nuclear DNA polymerases α, δ, and ε by causing DNA chain termination, resulting in inhibition of DNA synthesis (2). In rodent

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“…This observation has led to the exploration of immune-based cancer therapies in humans and dogs, including in canine LSA [28–31]. In the present study we have used immunosignatures to characterize canine LSA and evaluated the immunosignature technology as a diagnostic.…”

Section: Discussionmentioning

confidence: 99%

The immunosignature of canine lymphoma: characterization and diagnostic application

2014

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BackgroundCancer diagnosis in both dogs and humans is complicated by the lack of a non-invasive diagnostic test. To meet this clinical need, we apply the recently developed immunosignature assay to spontaneous canine lymphoma as clinical proof-of-concept. Here we evaluate the immunosignature as a diagnostic for spontaneous canine lymphoma at both at initial diagnosis and evaluating the disease free interval following treatment.MethodsSera from dogs with confirmed lymphoma (B cell n = 38, T cell n = 11) and clinically normal dogs (n = 39) were analyzed. Serum antibody responses were characterized by analyzing the binding pattern, or immunosignature, of serum antibodies on a non-natural sequence peptide microarray. Peptides were selected and tested for the ability to distinguish healthy dogs from those with lymphoma and to distinguish lymphoma subtypes based on immunophenotype. The immunosignature of dogs with lymphoma were evaluated for individual signatures. Changes in the immunosignatures were evaluated following treatment and eventual relapse.ResultsDespite being a clonal disease, both an individual immunosignature and a generalized lymphoma immunosignature were observed in each dog. The general lymphoma immunosignature identified in the initial set of dogs (n = 32) was able to predict disease status in an independent set of dogs (n = 42, 97% accuracy). A separate immunosignature was able to distinguish the lymphoma based on immunophenotype (n = 25, 88% accuracy). The individual immunosignature was capable of confirming remission three months following diagnosis. Immunosignature at diagnosis was able to predict which dogs with B cell lymphoma would relapse in less than 120 days (n = 33, 97% accuracy).ConclusionWe conclude that the immunosignature can serve as a multilevel diagnostic for canine, and potentially human, lymphoma.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-657) contains supplementary material, which is available to authorized users.

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Human granulocyte–macrophage colony-stimulating factor DNA cationic-lipid complexed autologous tumour cell vaccination in the treatment of canine B-cell multicentric lymphoma

Cited by 28 publications

References 55 publications

Randomized, Placebo-Controlled, Double-Blinded Chemoimmunotherapy Clinical Trial in a Pet Dog Model of Diffuse Large B-cell Lymphoma

Randomized, Placebo-Controlled, Double-Blinded Chemoimmunotherapy Clinical Trial in a Pet Dog Model of Diffuse Large B-cell Lymphoma

Assessment of GS-9219 in a Pet Dog Model of Non-Hodgkin's Lymphoma

The immunosignature of canine lymphoma: characterization and diagnostic application

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