PD‐1 blockade enhances the antitumor efficacy of GM‐CSF surface‐modified bladder cancer stem cells vaccine

Eliminating cancer stem cells (CSCs) is a key issue in eradicating tumor. The streptavidin–granulocyte‐macrophage‐colony stimulating factor (SA–GM‐CSF) surface‐modified bladder CSCs vaccine previously developed using our protein–anchor technology could effectively induce specific immune response for eliminating CSCs. However, program death receptor‐1 (PD‐1)/program death ligand 1 (PD‐L1) signaling in tumor microenvironment results in tumor‐adaptive immune resistance. Although the CSCs vaccine could increase the number of CD8⁺T cells, a part of these CD8⁺T cells expressed PD‐1. Moreover, the CSCs vaccine upregulated the PD‐L1 expression of tumor cells, resulting in immune resistance. Adding PD‐1 blockade to the CSCs vaccine therapy increased the population of CD4⁺, CD8⁺ and CD8⁺IFN‐γ⁺ but not CD4⁺ Foxp3⁺T cells and induced the highest production of IFN‐γ. PD‐1 blockade could effectively enhance the functions of tumor‐specific T lymphocytes generated by the CSCs vaccine. This combination therapy improved the cure rate among mice and effectively protected the mice against a second CSCs cell challenge, but not a RM‐1 cell challenge. These results indicate that PD‐1 blockade combined with the GM‐CSF‐modified CSCs vaccine effectively induced a strong and specific antitumor immune response against bladder cancer.     

Intratumoral COX‐2 inhibition enhances GM‐CSF immunotherapy against established mouse GL261 brain tumors

Immunotherapy has shown effectiveness against experimental malignant brain tumors, but the clinical results have been less convincing most likely due to immunosuppression. Prostaglandin E₂ (PGE₂) is the key immunosuppressive product of cyclooxygenase‐2 (COX‐2) and increased levels of PGE₂ and COX‐2 have been shown in several tumor types, including brain tumors. In the current study, we report enhanced cure rate of mice with established mouse GL261 brain tumors when immunized with granulocyte macrophage‐colony stimulating factor (GM‐CSF) secreting tumor cells and simultaneously treated with the selective COX‐2 inhibitors parecoxib systemically (5 mg/kg/day; 69% cure rate) or valdecoxib intratumorally (5.3 µg/kg/day; 63% cure rate). Both combined therapies induced a systemic antitumor response of proliferating CD4⁺ and CD8⁺ T cells, and further analysis revealed T helper 1 (T_h1) cell supremacy. The GL261 tumor cell line produced low levels of PGE₂ in vitro, and co‐staining at the tumor site demonstrated that a large fraction of the COX‐2⁺ cells were derived from CD45⁺ immune cells and more specifically macrophages (F4/80⁺), indicating that tumor‐infiltrating immune cells constitute the primary source of COX‐2 and PGE₂ in this model. We conclude that intratumoral COX‐2 inhibition potentiates GM‐CSF immunotherapy against established brain tumors at substantially lower doses than systemic administration. These findings underscore the central role of targeting COX‐2 during immunotherapy and implicate intratumoral COX‐2 as the primary target.     

Cancer‐associated fibroblast‐targeted strategy enhances antitumor immune responses in dendritic cell‐based vaccine

Given the close interaction between tumor cells and stromal cells in the tumor microenvironment (TME), TME‐targeted strategies would be promising for developing integrated cancer immunotherapy. Cancer‐associated fibroblasts (CAFs) are the dominant stromal component, playing critical roles in generation of the pro‐tumorigenic TME. We focused on the immunosuppressive trait of CAFs, and systematically explored the alteration of tumor‐associated immune responses by CAF‐targeted therapy. C57BL/6 mice s.c. bearing syngeneic E.G7 lymphoma, LLC1 Lewis lung cancer, or B16F1 melanoma were treated with an anti‐fibrotic agent, tranilast, to inhibit CAF function. The infiltration of immune suppressor cell types, including regulatory T cells and myeloid‐derived suppressor cells, in the TME was effectively decreased through reduction of stromal cell‐derived factor‐1, prostaglandin E₂, and transforming growth factor‐β. In tumor‐draining lymph nodes, these immune suppressor cell types were significantly decreased, leading to activation of tumor‐associated antigen‐specific CD8⁺ T cells. In addition, CAF‐targeted therapy synergistically enhanced multiple types of systemic antitumor immune responses such as the cytotoxic CD8⁺ T cell response, natural killer activity, and antitumor humoral immunity in combination with dendritic cell‐based vaccines; however, the suppressive effect on tumor growth was not observed in tumor‐bearing SCID mice. These data indicate that systemic antitumor immune responses by various immunologic cell types are required to bring out the efficacy of CAF‐targeted therapy, and these effects are enhanced when combined with effector‐stimulatory immunotherapy such as dendritic cell‐based vaccines. Our mouse model provides a novel rationale with TME‐targeted strategy for the development of cell‐based cancer immunotherapy.     

前列腺癌树突状细胞疫苗的研究进展

几乎所有晚期及复发前列腺癌患者发展成为激素非依耐性前列腺癌,甚至部分患者继续发展为HRPC。目前对HRPC尚无完全有效治疗手段。近年来前列腺癌的免疫治疗,特别是基于树突状细胞的免疫疗法取得了快速进展并应用于临床,本文就前列腺癌树突状细胞疫苗的研究进展做一综述。     

Integrated data from 2 randomized,double‐blind,placebo‐controlled,phase 3 trials of active cellular immunotherapy with sipuleucel‐T in advanced prostate cancer

BACKGROUND:

Sipuleucel‐T is an investigational active cellular immunotherapy product designed to stimulate an immune response against prostate cancer. The safety and efficacy of sipuleucel‐T was evaluated in 2 identically designed, randomized, double‐blind, placebo‐controlled trials (D9901 and D9902A) conducted in men with advanced prostate cancer.

METHODS:

A total of 225 patients were randomized in D9901 or D9902A to sipuleucel‐T (n = 147) or placebo (n = 78), given as 3 intravenous infusions approximately 2 weeks apart. Patients were followed for survival until death or a prespecified cutoff of 36 months after randomization.

RESULTS:

In the integrated analysis of D9901 and D9902A, patients randomized to sipuleucel‐T demonstrated a 33% reduction in the risk of death (hazard ratio, 1.50; 95% confidence interval, 1.10‐2.05; P = .011; log‐rank). The treatment effect remained strong after performing adjustments for imbalances in baseline prognostic factors, poststudy treatment chemotherapy use, and non–prostate cancer‐related deaths. Additional support for the activity of sipuleucel‐T is provided by the correlation between a measure of the product's potency, CD54 up‐regulation, and overall survival. The most common adverse events associated with treatment were chills, pyrexia, headache, asthenia, dyspnea, vomiting, and tremor. These events were primarily grade 1 and 2, with durations of 1 to 2 days.

CONCLUSIONS:

The integrated results of D9901 and D9902A demonstrate a survival benefit for patients treated with sipuleucel‐T compared with those treated with placebo. The generally modest toxicity profile, coupled with the survival benefit, suggests a favorable risk‐benefit ratio for sipuleucel‐T in patients with advanced prostate cancer. Cancer 2009. © 2009 American Cancer Society.     

Serotype chimeric oncolytic adenovirus coding for GM‐CSF for treatment of sarcoma in rodents and humans

Sarcomas are a relatively rare cancer, but often incurable at the late metastatic stage. Oncolytic immunotherapy has gained attention over the past years, and a wide range of oncolytic viruses have been delivered via intratumoral injection with positive safety and promising efficacy data. Here, we report preclinical and clinical results from treatment of sarcoma with oncolytic adenovirus Ad5/3‐D24‐GMCSF (CGTG‐102). Ad5/3‐D24‐GMCSF is a serotype chimeric oncolytic adenovirus coding for human granulocyte‐macrophage colony‐stimulating factor (GM‐CSF). The efficacy of Ad5/3‐D24‐GMCSF was evaluated on a panel of soft‐tissue sarcoma (STS) cell lines and in two animal models. Sarcoma specific human data were also collected from the Advanced Therapy Access Program (ATAP), in preparation for further clinical development. Efficacy was seen in both in vitro and in vivo STS models. Fifteen patients with treatment‐refractory STS (13/15) or primary bone sarcoma (2/15) were treated in ATAP, and treatments appeared safe and well‐tolerated. A total of 12 radiological RECIST response evaluations were performed, and two cases of minor response, six cases of stable disease and four cases of progressive disease were detected in patients progressing prior to virus treatment. Overall, the median survival time post treatment was 170 days. One patient is still alive at 1,459 days post virus treatment. In summary, Ad5/3‐D24‐GMCSF appears promising for the treatment of advanced STS; a clinical trial for treatment of refractory injectable solid tumors including STS is ongoing.© 2013 UICC     

Enhanced antitumor effects by the coculture of allotumor RNA-pulsed dendritic cells with autologous cytokine-induced killer cells on hormone-refractory prostate cancer

In this study, we evaluated antitumor effects of allotumour RNA-transfected dendritic cells (DCs) cocultured with autologous cytokine-induced killer cells (CIKs) on hormone-refractory prostate cancer. The cocultured cells enhanced prostate cancer cytolysis from 26% (CIKs-induced cytolysis) to 80.8%. They also increased the productions of CD4⁺ Th1 (IFN-γ⁺IL-4^-, 55.52%) and CD8⁺ T (IFN-γ⁺, 69.59%) cells determined by intracellular cytokines IFN-γ /IL-4 staining and reduced the rate of CD4⁺ CD25⁺ cells from 18.72% (in CIKs) to 9.72%. The cocultured cells significantly inhibited tumor growth in SCID mouse and induced cancer cells necrosis and apoptosis. Our study indicates that tumor RNA-pulsed DCs cocultured with autologous CIKs significantly enhance antitumor immunity, which can be induced by increased CD4⁺ Th1 and CD8⁺ T cells and decreased CD4⁺CD25⁺ regulatory T (T_reg) cells. This provides a potential immunotherapy strategy for HRPC.     

Messenger RNA vaccine based on recombinant MS2 virus‐like particles against prostate cancer

Prostate cancer (PCa) is the most diagnosed cancer in the western male population with high mortality. Recently, alternative approaches based on immunotherapy including mRNA vaccines for PCa have shown therapeutic promise. However, for mRNA vaccine, several disadvantages such as the instability of mRNA, the high cost of gold particles, the limited production scale for mRNA‐transfected dendritic cells in vitro, limit their development. Herein, recombinant bacteriophage MS2 virus‐like particles (VLPs), which based on the interaction of a 19‐nucleotide RNA aptamer and the coat protein of bacteriophage MS2, successfully addressed these questions, in which target mRNA was packaged by MS2 capsid. MS2 VLP‐based mRNA vaccines were easily prepared by recombinant protein technology, nontoxic and RNase‐resistant. We show the packaged mRNA was translated into protein as early as 12 hr after phagocytosed by macrophages. Moreover, MS2 VLP‐based mRNA vaccines induced strong humoral and cellular immune responses, especially antigen‐specific cytotoxic T‐lymphocyte (CTL) and balanced Th1/Th2 responses without upregulation of CD4⁺ regulatory T cells, and protected C57BL/6 mice against PCa completely. As a therapeutic vaccine, MS2 VLP‐based mRNA vaccines delayed tumor growth. Our results provide proof of concept on the efficacy and safety of MS2 VLP‐based mRNA vaccine, which provides a new delivery approach for mRNA vaccine and implies important clinical value for the prevention and therapy of PCa.     

ERK inhibitor PD98059 enhances docetaxel-induced apoptosis of androgen-independent human prostate cancer cells

Anticancer drugs docetaxel and vinorelbine suppress cell growth by altering microtubule assembly and activating the proapoptotic signal pathway. Vinorelbine and docetaxel have been approved for treating several advanced cancers. However, their efficacy in the management of advanced hormone-refractory prostate cancer remains to be clarified. Microtubule damage by some anticancer drugs can activate the ERK survival pathway, which conversely compromises chemotherapeutic efficacy. We analyzed the effect of ERK inhibitors PD98059 and U0126 on vinorelbine- and docetaxel-induced cell growth suppression of androgen-independent prostate cancer cells. In androgen-independent C-81 LNCaP cells, inhibition of ERK by PD98059, but not U0126, plus docetaxel resulted in enhanced growth suppression by an additional 20% compared to the sum of each agent alone (p < 0.02). The combination treatment of docetaxel plus PD98059 also increased cellular apoptosis, which was in part due to the inactivation of Bcl-2 by increasing phosphorylated Bcl-2 by more than 6-fold and Bax expression by 3-fold over each agent alone. At these dosages, docetaxel alone caused only marginal phosphorylation of Bcl-2 (10%). Docetaxel plus U0126 had only 20% added effect on Bcl-2 phosphorylation compared to docetaxel alone. Nevertheless, both U0126 and PD98059 exhibited an enhanced effect on docetaxel-induced growth suppression in PC-3 cells. No enhanced effect was observed for vinorelbine plus PD98059 or U0126. Thus, the combination therapy of docetaxel plus PD98059 may represent a new anticancer strategy, requiring lower drug dosages compared to docetaxel monotherapy. This may lower the cytotoxicity and enhance tumor suppression in vivo. This finding of a combination effect could be of potential clinical importance in treating hormone-refractory prostate cancer.     

Oncolytic activity of the rhabdovirus VSV‐GP against prostate cancer

Oncolytic viruses, including the oncolytic rhabdovirus VSV‐GP tested here, selectively infect and kill cancer cells and are a promising new therapeutic modality. Our aim was to study the efficacy of VSV‐GP, a vesicular stomatitis virus carrying the glycoprotein of lymphocytic choriomeningitis virus, against prostate cancer, for which current treatment options still fail to cure metastatic disease. VSV‐GP was found to infect 6 of 7 prostate cancer cell lines with great efficacy. However, susceptibility was reduced in one cell line with low virus receptor expression and in 3 cell lines after interferon alpha treatment. Four cell lines had developed resistance to interferon type I at different levels of the interferon signaling pathway, resulting in a deficient antiviral response. In prostate cancer mouse models, long‐term remission was achieved upon intratumoral and, remarkably, also upon intravenous treatment of subcutaneous tumors and bone metastases. These promising efficacy data demonstrate that treatment of prostate cancer with VSV‐GP is feasible and safe in preclinical models and encourage further preclinical and clinical development of VSV‐GP for systemic treatment of metastatic prostate cancer.     

Norcantharidin inhibits proliferation and promotes apoptosis via c‐Met/Akt/mTOR pathway in human osteosarcoma cells

Osteosarcoma (OS) is the most common malignant bone tumor and frequently affects adolescents. Norcantharidin (NCTD), a demethylated derivative of cantharidin, has been reported to exhibit anticancer activity against various types of tumors but not human OS. The aim of the present study was to evaluate the effects of NCTD on OS cell lines (MG63 and HOS) and to explore the underlying mechanisms. In the present study, the proliferation of OS cells decreased significantly, while the apoptosis was accelerated significantly after exposure to NCTD. Meanwhile, our results also indicated that NCTD could suppress the migration and invasion, decrease the colony‐forming ability and induce S phase cell cycle arrest of OS cells in a dose‐dependent manner. Moreover, our results revealed that the anticancer effects induced by NCTD on OS cells involved autophagy, mitophagy, endoplasmic reticulum stress and c‐Met pathway. Furthermore, the results of animal experiments showed that NCTD inhibited tumor growth in a xenograft model of human OS. These results provide important new insight into the possible molecular mechanisms of NCTD and highlight its potential use as an antitumor drug for human OS.     

Exosomal circGSE1 promotes immune escape of hepatocellular carcinoma by inducing the expansion of regulatory T cells

Studies have shown exosomal circRNAs can regulate the immune escape of tumors by carrying cancer‐derived molecules. Regulatory T cells (Tregs) participate in the process of tumor immune escape. However, the mechanism by which exosomal circRNAs regulate Tregs to create a microenvironment for tumor immune escape is unclear. The effect of exosomes on the proliferation, migration, and invasion of tumor cells was evaluated by CCK‐8, transwell, and wound‐healing assays. The expression of circGSE1 was evaluated by real‐time quantitative PCR, and the function of exosomal circGSE1 was explored by Western blot and RNA pull‐down assays. In vivo animal metastasis models and bioluminescence imaging were used to verify the effect of exosomal circGSE1 on tumor progression. Collectively, we revealed that exosomal circGSE1 derived from hepatocellular carcinoma (HCC) cells promotes the progression of HCC by inducing Tregs expansion via regulating the miR‐324‐5p/TGFBR1/Smad3 axis. Therefore, in the future, exosomal circGSE1 can be used as a promising biomarker for immunotherapy of HCC.     

The antitumor potential of Interleukin-27 in prostate cancer

Prostate cancer (PCa) is of increasing significance worldwide as a consequence of the population ageing. Fragile elderly patients may particularly benefit from noninvasive and well tolerable immunotherapeutic approaches. Preclinical studies have revealed that the immune-regulatory cytokine IL-27 may exert anti-tumor activities in a variety of tumor types without discernable toxicity. We, thus, investigated whether IL-27 may function as anti-tumor agent in human (h) PCa and analyzed the rationale for its clinical application.In vitro, IL-27 treatment significantly inhibited proliferation and reduced the angiogenic potential of hPCa cells by down-regulating the pro-angiogenesis-related genes fms-related tyrosine kinase (FLT)1, prostaglandin G/H synthase 1/cyclooxygenase-1 (PTGS1/COX-1) and fibroblast growth factor receptor (FGFR)3. In addition, IL-27 up-regulated the anti-angiogenesis-related genes such as CXCL10 and TIMP metallopeptidase inhibitor 3 (TIMP3). In vivo, IL-27 reduced proliferation and vascularization in association with ischemic necrosis of tumors developed after PC3 or DU145 cell injection in athymic nude mice. In patients'' prostate tissues, IL-27R was expressed by normal epithelia and low grade PCa and lost by high tumor grade and stages. Nevertheless, IL-27R was expressed by CD11c⁺, CD4⁺ and CD8⁺ leukocytes infiltrating the tumor and draining lymph nodes.These data lead to the conclusion that i) IL-27''s anti-PCa potential may be fully exploited in patients with well-differentiated, localized IL-27R positive PCa, since in this case it may act on both cancerous epithelia and the tumor microenvironment; ii) PCa patients bearing high grade and stage tumor that lack IL-27R may benefit, however, from IL-27''s immune-stimulatory properties.     

Leucinostatin A inhibits prostate cancer growth through reduction of insulin‐like growth factor‐I expression in prostate stromal cells

Targeting stroma in tumor tissues is an attractive new strategy for cancer treatment. We developed in vitro coculture system, in which the growth of human prostate cancer DU‐145 cells is stimulated by prostate stromal cells (PrSC) through insulin‐like growth factor I (IGF‐I). Using this system, we have been searching for small molecules that inhibit tumor growth through modulation of tumor‐stromal cell interactions. As a result, we have found that leucinostatins and atpenins, natural antifungal antibiotics, inhibit the growth of DU‐145 cells cocultured with PrSC more strongly than that of DU‐145 cells alone. In this study we examined the antitumor effects of these small molecules in vitro and in vivo. When DU‐145 cells were coinoculated with PrSC subcutaneously in nude mice, leucinostatin A was found to significantly suppress the tumor growth more than atpenin B. The antitumor effect of leucinostatin A in vivo was not obtained against the tumors of DU‐145 cells alone. RT‐PCR experiments revealed that leucinostatin A specifically inhibited IGF‐I expression in PrSC without effect on expressions of other IGF axis molecules. Leucinostatins and atpenins are known to abrogate mitochondrial functions. However, when we used mitochondrial DNA‐depleted, pseudo‐ρ⁰ cells, we found that one of leucinostain A actions certainly depended on mitochondrial function, but it actually inhibited the growth of DU‐145 cells more strongly in coculture with pseudo‐ρ⁰ PrSC and reduced IGF‐I expression in pseudo‐ρ⁰ PrSC. Taken together, our results suggested that leucinostatin A inhibited prostate cancer cell growth through reduction of IGF‐I expression in PrSC.     

Secreted factors from metastatic prostate cancer cells stimulate mesenchymal stem cell transition to a pro‐tumourigenic ‘activated’ state that enhances prostate cancer cell migration

Mesenchymal stem cells (MSCs) are a heterogeneous population of multipotent cells that are capable of differentiating into osteocytes, chondrocytes and adipocytes. Recently, MSCs have been found to home to the tumour site and engraft in the tumour stroma. However, it is not yet known whether they have a tumour promoting or suppressive function. We investigated the interaction between prostate cancer cell lines 22Rv1, DU145 and PC3, and bone marrow‐derived MSCs. MSCs were ‘educated’ for extended periods in prostate cancer cell conditioned media and PC3‐educated MSCs were found to be the most responsive with a secretory profile rich in pro‐inflammatory cytokines. PC3‐educated MSCs secreted increased osteopontin (OPN), interleukin‐8 (IL‐8) and fibroblast growth factor‐2 (FGF‐2) and decreased soluble fms‐like tyrosine kinase‐1 (sFlt‐1) compared to untreated MSCs. PC3‐educated MSCs showed a reduced migration and proliferation capacity that was dependent on exposure to PC3‐conditioned medium. Vimentin and α‐smooth muscle actin (αSMA) expression was decreased in PC3‐educated MSCs compared to untreated MSCs. PC3 and DU145 education of healthy donor and prostate cancer patient‐derived MSCs led to a reduced proportion of FAP+ αSMA+ cells contrary to characteristics commonly associated with cancer associated fibroblasts (CAFs). The migration of PC3 cells was increased toward both PC3‐educated and DU145‐educated MSCs compared to untreated MSCs, while DU145 migration was only enhanced toward patient‐derived MSCs. In summary, MSCs developed an altered phenotype in response to prostate cancer conditioned medium which resulted in increased secretion of pro‐inflammatory cytokines, modified functional activity and the chemoattraction of prostate cancer cells.     

Treatment of melanoma with a serotype 5/3 chimeric oncolytic adenovirus coding for GM‐CSF: Results in vitro,in rodents and in humans

Metastatic melanoma is refractory to irradiation and chemotherapy, but amenable to immunological approaches such as immune‐checkpoint‐inhibiting antibodies or adoptive cell therapies. Oncolytic virus replication is an immunogenic phenomenon, and viruses can be armed with immunostimulatory molecules. Therefore, oncolytic immuno‐virotherapy of malignant melanoma is an appealing approach, which was recently validated by a positive phase 3 trial. We investigated the potency of oncolytic adenovirus Ad5/3‐D24‐GMCSF on a panel of melanoma cell lines and animal models, and summarized the melanoma‐specific human data from the Advanced Therapy Access Program (ATAP). The virus effectively eradicated human melanoma cells in vitro and subcutaneous SK‐MEL‐28 melanoma xenografts in nude mice when combined with low‐dose cyclophosphamide. Furthermore, virally‐expressed granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) stimulated the differentiation of human monocytes into macrophages. In contrast to human cells, RPMI 1846 hamster melanoma cells exhibited no response to oncolytic viruses and the chimeric 5/3 fiber failed to increase the efficacy of transduction, suggesting limited utility of the hamster model in the context of viruses with this capsid. In ATAP, treatments appeared safe and well‐tolerated. Four out of nine melanoma patients treated were evaluable for possible therapy benefit with modified RECIST criteria: one patient had minor response, two had stable disease, and one had progressive disease. Two patients were alive at 559 and 2,149 days after treatment. Ad5/3‐D24‐GMCSF showed promising efficacy in preclinical studies and possible antitumor activity in melanoma patients refractory to other forms of therapy. This data supports continuing the clinical development of oncolytic adenoviruses for treatment of malignant melanoma.     

Delphinidin sensitizes prostate cancer cells to TRAIL-induced apoptosis,by inducing DR5 and causing caspase-mediated HDAC3 cleavage

TRAIL can induce apoptosis in some cancer cells and is an immune effector in the surveillance and elimination of developing tumors. Yes, some cancers are resistant to TRAIL. Delphinidin, a polyphenolic compound contained in brightly colored fruits and vegetables, has anti-inflammatory, anti-oxidant, and anti-tumorigenic activities. Here we showed that delphinidin sensitized TRAIL-resistant human prostate cancer cells to undergo apoptosis. Cells treated with delphinidin and TRAIL activated the extrinsic and intrinsic pathways of caspase activation. TRAIL-induced apoptosis in prostate cancer cells pretreated with delphinidin was dependent on death receptor 5 (DR5) and downstream cleavage of histone deacetylase 3 (HDAC3). In conclusion, delphinidin sensitizes prostate cancer cells to TRAIL-induced apoptosis by inducing DR5, thus causing caspase-mediated HDAC3 cleavage. Our data reveal a potential way of chemoprevention of prostate cancer by enabling TRAIL-mediated apoptosis.     

Early phase II study of mixed 19‐peptide vaccine monotherapy for refractory triple‐negative breast cancer

We undertook an early phase II study of mixed 19‐peptide cancer vaccine monotherapy for 14 advanced metastatic triple‐negative breast cancer (mTNBC) patients refractory to systemic chemotherapy to develop a new type of cancer vaccine. The treatment protocol consisted of a weekly vaccination for 6 weeks, and there were no severe adverse events related to the vaccination throughout the trial. Increase of peptide‐specific IgG against the vaccinated human leukocyte antigen‐matched peptides, but not against the nonmatched peptides, was positively correlated with overall survival (OS) (P < .01). The median OS was 11.5 or 24.4 months in all 14 patients or the 10 patients who completed the vaccination. The patients with lower C‐reactive protein levels or 3 or fewer systemic chemotherapies were favorable candidates for this treatment. Advancement of this therapy to the next stage of study could be warranted based on the safety and immune boosting determined herein (clinical trial registration number: UMIN000014616).