Secreted heat shock protein gp96-Ig: next-generation vaccines for cancer and infectious diseases

Štrbo, Nataša; Garcia-Soto, A.E.; Schreiber, Taylor H.; Podack, Eckhard R.

doi:10.1007/s12026-013-8468-x

Cited by 36 publications

(48 citation statements)

References 123 publications

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“…Gp96-cancer antigen complexes have been identified as efficient stimulators of CD8 cytotoxic T cell production via tumor antigen cross-presentation on MHC class I. [62] The ongoing phase I and II trials aim to evaluate the safety and efficacy of HS-410 with standard intravesical BCG in BCG-naïve patients with intermediate to high risk NMIBC. At the recent SUO Annual Meeting in 2016, the investigators of this trial reported on 1-year recurrence-free survival across all arms to be 84.6% with no difference between BCG alone and BCG with HS-410 arms.…”

Section: Bcg-naïve or -Unresponsivementioning

confidence: 99%

Current clinical trials in non–muscle invasive bladder cancer

Siddiqui

Grant

Sanford

et al. 2017

Urologic Oncology: Seminars and Original Investigations

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Background The treatment options for non-muscle invasive bladder cancer (NMIBC) remain limited. BCG was the last major breakthrough in bladder cancer therapy almost 4 decades ago. There have been improvements in the understanding of immune therapies and cancer biology, leading to the development of novel agents. This has led to many clinical trials that are currently underway to find the next generation of therapies for NMIBC. Method We reviewed clinicaltrials.org and pubmed.gov to find the recently completed and ongoing clinical trials in NIMBC. Included in this review are clinical trials that are currently active and trials that were completed in and after 2014. Result Many trials with BCG naïve and BCG unresponsive/recurrent/refractory/failure NMIBC patients are either currently underway or have been recently completed. A wide variety of novel therapeutic agents are being investigated that range from cytotoxic agents to immunomodulatory agents to targeted molecular therapies. Other approaches include cancer vaccines, gene therapies, and chemoradiation potentiation agents. Novel drug delivery methods are also being tested. Conclusion This comprehensive update of current trials provides researchers an overview of the current clinical trial landscape for patients with NMIBC.

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Section: Bcg-naïve or -Unresponsivementioning

confidence: 99%

Current clinical trials in non–muscle invasive bladder cancer

Siddiqui

Grant

Sanford

et al. 2017

Urologic Oncology: Seminars and Original Investigations

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“…HIV cellular tropism, rapid escape mutations, and viral latency are major prevention and treatment hurdles (3)(4)(5)(6). Here we used transcriptional profiling of host responses to vaccination and subsequent repeated challenges to further understand the protective effects of a novel vaccination strategy based on the use of the endoplasmic reticulum resident chaperone gp96 (7). This heat shock protein, similar to soluble Hsfp and hsp65 (8,9), binds to and activates dendritic cells (10) and functions as a chaperone for tumor-secreted peptides.…”

mentioning

confidence: 99%

Multiple Low-Dose Challenges in a Rhesus Macaque AIDS Vaccine Trial Result in an Evolving Host Response That Affects Protective Outcome

Selinger

Štrbo

Gonzalez

et al. 2014

Clin. Vaccine Immunol.

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dUsing whole-blood transcriptional profiling, we investigated differences in the host response to vaccination and challenge in a rhesus macaque AIDS vaccine trial. Samples were collected from animals prior to and after vaccination with live, irradiated vaccine cells secreting the modified endoplasmic reticulum chaperone gp96-Ig loaded with simian immunodeficiency virus (SIV) peptides, either alone or in combination with a SIV-gp120 protein boost. Additional samples were collected following multiple low-dose rectal challenges with SIV mac251 . Animals in the boosted group had a 73% reduced risk of infection. Surprisingly, few changes in gene expression were observed during the vaccination phase. Focusing on postchallenge comparisons, in particular for protected animals, we identified a host response signature of protection comprised of strong interferon signaling after the first challenge, which then largely abated after further challenges. We also identified a host response signature, comprised of early macrophage-mediated inflammatory responses, in animals with undetectable viral loads 5 days after the first challenge but with unusually high viral titers after subsequent challenges. Statistical analysis showed that prime-boost vaccination significantly lowered the probability of infection in a time-consistent manner throughout several challenges. Given that humoral responses in the prime-boost group were highly significant prechallenge correlates of protection, the strong innate signaling after the first challenge suggests that interferon signaling may enhance vaccine-induced antibody responses and is an important contributor to protection from infection during repeated low-dose exposure to SIV.

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“…Except for a few epitopes from viral or model antigens, the tumor-specific epitopes, like the shared epitopes in SLiPs we proposed here, remain as a mystery47. Of note, results from Podack’s group indicated that gp96 could also present shared epitopes when gp96 was fused with IgG Fc and secreted from allogeneic tumor cells48. Thus, it is reasonable to propose that HSPs and ubiquitinated SLiPs in DRibbles may represent two different pools of antigens- we hypothesized that HSPs purified from tumor cells contain tumor-specific antigens that are not shared among tumor cells, and therefore would be expected to provide protection only from the same tumor challenges; whereas SLiPs provide shared antigens and can elicit cross-protection against challenge with different types of tumors, including allogeneic tumor cells.…”

Section: Discussionmentioning

confidence: 62%

Combinational Immunotherapy with Allo-DRibble Vaccines and Anti-OX40 Co-Stimulation Leads to Generation of Cross-Reactive Effector T Cells and Tumor Regression

Cui

et al. 2016

Sci Rep

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It is well-known that vaccines comprising of irradiated whole tumor cells or tumor-derived heat shock proteins can generate tumor-specific immune responses. In contrast, we showed recently that vaccines composed of autophagosomes (DRibbles) derived from syngeneic sarcomas could induce cross-reactive T-cell responses and cross-protection against the tumor. This unusual property of DRibbles was related to the selective recruitment of defective ribosomal products (DRiPs) and other short-lived proteins (SLiPs) into autophagosomes via sequestosome (SQSTM1, p62) mediated association of ubiquitinated SLiPs to the autophagy gene product LC3. Here, we extend our observations to mammary carcinomas from mice of different genetic background. We demonstrated that combined of intranodal administration of autologous or allogeneic DRibbles together with anti-OX40 antibody led to robust proliferation, expansion, and differentiation of memory and effector T cells. We also showed that SLiPs is an excellent source of antigen for cross-priming of CD8+ T-cells that recognize shared tumor antigens in the context of host MHC class I molecules. Thus, our results provide a strong basis for novel clinical trials that combine allogeneic “off-the-shelf” DRibble vaccines together with antibodies against co-stimulatory molecules.

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Secreted heat shock protein gp96-Ig: next-generation vaccines for cancer and infectious diseases

Cited by 36 publications

References 123 publications

Current clinical trials in non–muscle invasive bladder cancer

Current clinical trials in non–muscle invasive bladder cancer

Multiple Low-Dose Challenges in a Rhesus Macaque AIDS Vaccine Trial Result in an Evolving Host Response That Affects Protective Outcome

Combinational Immunotherapy with Allo-DRibble Vaccines and Anti-OX40 Co-Stimulation Leads to Generation of Cross-Reactive Effector T Cells and Tumor Regression

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