In Situ Vaccination With a TLR9 Agonist Induces Systemic Lymphoma Regression: A Phase I/II Study

Brody, Joshua; Ai, Weiyun Z.; Czerwinski, Debra K.; Torchia, James A.; Levy, Mia A.; Advani, Ranjana H.; Kim, Youn H.; Hoppe, Richard T.; Knox, Susan J.; Shin, Lewis K.; Wapnir, Irene; Tibshirani, Robert; Levy, Ronald

doi:10.1200/jco.2010.28.9793

Cited by 456 publications

(336 citation statements)

References 40 publications

Supporting

Mentioning

324

Contrasting

Unclassified

Order By: Relevance

“…In line with this, we observed, within primary FL tumors harboring homozygous CREBBP mutations, that malignant B cells expressed ∼10-fold lower surface HLA-DR levels compared with nonmalignant counterparts from the same microenvironment. Interestingly, MHC class II deficit in CREBBP mutant cases could be overcome by stimulation with TLR ligand; a maneuver that has been used clinically to increase expression of costimulatory molecules and that has been shown to induce measurable clinical responses in a subset of FL patients (35). These observations add additional evidence supporting the importance of nonmalignant immune cells in these tumors (1-3) but provide the first evidence to our knowledge for CREBBP mutations contributing to immune evasion in FL.…”

Section: Discussionmentioning

confidence: 45%

Mutations in early follicular lymphoma progenitors are associated with suppressed antigen presentation

Green

Kihira²,

Liu³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

325

372

View full text Add to dashboard Cite

Follicular lymphoma (FL) is incurable with conventional therapies and has a clinical course typified by multiple relapses after therapy. These tumors are genetically characterized by B-cell leukemia/lymphoma 2 (BCL2) translocation and mutation of genes involved in chromatin modification. By analyzing purified tumor cells, we identified additional novel recurrently mutated genes and confirmed mutations of one or more chromatin modifier genes within 96% of FL tumors and two or more in 76% of tumors. We defined the hierarchy of somatic mutations arising during tumor evolution by analyzing the phylogenetic relationship of somatic mutations across the coding genomes of 59 sequentially acquired biopsies from 22 patients. Among all somatically mutated genes, CREBBP mutations were most significantly enriched within the earliest inferable progenitor. These mutations were associated with a signature of decreased antigen presentation characterized by reduced transcript and protein abundance of MHC class II on tumor B cells, in line with the role of CREBBP in promoting class II transactivator (CIITA)-dependent transcriptional activation of these genes. CREBBP mutant B cells stimulated less proliferation of T cells in vitro compared with wild-type B cells from the same tumor. Transcriptional signatures of tumor-infiltrating T cells were indicative of reduced proliferation, and this corresponded to decreased frequencies of tumor-infiltrating CD4 helper T cells and CD8 memory cytotoxic T cells. These observations therefore implicate CREBBP mutation as an early event in FL evolution that contributes to immune evasion via decreased antigen presentation. lymphoma | exome | hierarchy | antigen presentation | CREBBP

show abstract

Section: Discussionmentioning

confidence: 45%

Mutations in early follicular lymphoma progenitors are associated with suppressed antigen presentation

Green

Kihira²,

Liu³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

325

372

View full text Add to dashboard Cite

show abstract

“…Other innate immune pathway activators are being tested in the clinic as single agents or in combination with other therapies, with the aim to boost anti-tumor T cell responses [110][111][112]. Similar to STING agonists, intratumoral injection of TLR agonists such as CpG-rich oligodeoxynucleotides (CpG ODN, PF-3512676) along with low-dose radiotherapy has shown clinical responses in patients with advanced non-Hodgkin's lymphoma in a phase I/II clinical study [113].…”

Section: Therapeutic Opportunitiesmentioning

confidence: 99%

Innate immune signaling and regulation in cancer immunotherapy

et al. 2016

View full text Add to dashboard Cite

A pre-existing T cell-inflamed tumor microenvironment has prognostic utility and also can be predictive for response to contemporary cancer immunotherapies. The generation of a spontaneous T cell response against tumor-associated antigens depends on innate immune activation, which drives type I interferon (IFN) production. Recent work has revealed a major role for the STING pathway of cytosolic DNA sensing in this process. This cascade of events contributes to the activation of Batf3-lineage dendritic cells (DCs), which appear to be central to anti-tumor immunity. Non-T cell-inflamed tumors lack chemokines for Batf3 DC recruitment, have few Batf3 DCs, and lack a type I IFN gene signature, suggesting that failed innate immune activation may be the ultimate cause for lack of spontaneous T cell activation and accumulation. With this information in hand, new strategies for triggering innate immune activation and Batf3 DC recruitment are being developed, including novel STING agonists for de novo immune priming. Ultimately, the successful development of effective innate immune activators should expand the fraction of patients that can respond to immunotherapies, such as with checkpoint blockade antibodies.

show abstract

“…These reagents were employed also in a recent phase I study of in situ vaccination, which consists of low-dose irradiation to a single lymphoma site, followed by intratumoral injection of CpG at the same site. The first results were encouraging and showed that the in situ vaccination was able to induce tumor-reactive CD8 + T cells [54]. In addition, incorporation of Id into cytokine-carrying liposomes has been proposed as a tool to enhance Id delivery [37].…”

Section: Introduction________________________________________________mentioning

confidence: 76%

1086 IGHV1-69 as a Promising Candidate for the Development of a Shared Immunotherapy to B-cell Lymphomas

Muraro¹,

Martorelli²,

Bomben³

et al. 2012

European Journal of Cancer

View full text Add to dashboard Cite

B-cell Non-Hodgkin Lymphomas (B-NHL) are a heterogeneous group of cancers, broadly diffused worldwide and often relapsing after standard treatment and rituximab. Therapeutic vaccines targeting B-NHL idiotype (Id) represent a promising approach to maintain the complete response induced by standard treatments. However, customized idiotypic vaccination still remains a non-approved, experimental therapeutic option, mostly due to the personalized use and penalized by the lack of reliable clinical or biological markers of patient eligibility and responsiveness. Nevertheless, the molecular characterization of different lymphoid tumor histotypes revealed a set of stereotyped immunoglobulins among distinct B-cell lymphoma types. On this ground, we focused our attention on the IGHV1-69 protein, frequently expressed in HCV-associated lymphomas, chronic lymphocytic leukaemia, and auto-immunity related lymphoproliferations, and we characterized the ex vivo immunogenicity of this protein.Seventy IGHV1-69 sequences obtained from patients affected by different B-NHLs or pre-malignant lymphoproliferations were compared to design an optimized sequence characterized by the highest degree of similarity among studied cancers, and thus CDR3 hypervariable region free. Within this "immunogenically" optimized sequence, we identified 13 potential HLA class-I cytotoxic T lymphocyte (CTL) epitopes and synthesized the corresponding pentamers (Pent). We assessed by flow cytometry the presence and extent of epitope-specific T-cell responses in peripheral blood of patients with IGHV1-69 + B-cell lymphoproliferative disorders and healthy donors, and validated these data in IFN-γ ELISPOT (Enzyme-linked immunosorbent spot) assays. Finally, we boosted in vitro IGHV1-69-specific responses by stimulating peripheral blood lymphocytes (PBL) from donors and patients with different protocols for the generation of epitope-specific CTL cultures.Interestingly, the IGHV1-69 Pent + population observed in patients' samples was generally larger than in donors, supporting the existence of spontaneous memory T-cell responses against IGHV1-69, at least for some HLA-restrictions. Surprisingly, in patients' samples, IGHV1-69-recognizing T cells displayed higher IFN-γ release in ELISPOT assays compared to viral-specific T cells. Moreover, we obtained peptide-specific CTL lines, which showed a weak but specific lysis against peptide-pulsed targets, especially when derived from patients' PBLs. In addition, we were able to generate IGHV1-69-epitope specific CTL clones from healthy donors CD8 + T cells, employing synthetic artificial APC, developed to elicit and expand low-avidity tumor-directed human CTL lines. Finally, IGHV1-69-induced CTL lines showed specific lysis also towards an IGHV1-69 naturally expressing cell line, suggesting that IGHV1-69 memory T-cell responses could be boosted for therapeutic purposes.These results show that IGHV1-69 constitutes a potential target for the development of a subset-specific Id vaccine. Furthermore, multimer (tetramers...

show abstract

In Situ Vaccination With a TLR9 Agonist Induces Systemic Lymphoma Regression: A Phase I/II Study

Cited by 456 publications

References 40 publications

Mutations in early follicular lymphoma progenitors are associated with suppressed antigen presentation

Mutations in early follicular lymphoma progenitors are associated with suppressed antigen presentation

Innate immune signaling and regulation in cancer immunotherapy

1086 IGHV1-69 as a Promising Candidate for the Development of a Shared Immunotherapy to B-cell Lymphomas

Contact Info

Product

Resources

About