Vaccines For Cancer Immunotherapy Research Articles

Quality Verification with a Cluster-Controlled Manufacturing System to Generate Monocyte-Derived Dendritic Cells.

Dendritic cell (DC) vaccines for cancer immunotherapy have been actively developed to improve clinical efficacy. In our previous report, monocyte−derived DCs induced by interleukin (IL)−4 with a low−adherence dish (low−adherent IL-4−DCs: la−IL-4−DCs) improved the yield and viability, as well as relatively prolonged survival in vitro, compared to IL-4−DCs developed using an adherent culture protocol. However, la−IL-4−DCs exhibit remarkable cluster formation and display heterogeneous immature phenotypes. Therefore, cluster formation in la−IL-4−DCs needs to be optimized for the clinical development of DC vaccines. In this study, we examined the effects of cluster control in the generation of mature IL-4−DCs, using cell culture vessels and measuring spheroid formation, survival, cytokine secretion, and gene expression of IL-4−DCs. Mature IL-4−DCs in cell culture vessels (cluster−controlled IL-4−DCs: cc−IL-4−DCs) displayed increased levels of CD80, CD86, and CD40 compared with that of la−IL-4−DCs. cc−IL-4−DCs induced antigen−specific cytotoxic T lymphocytes (CTLs) with a human leukocyte antigen (HLA)−restricted melanoma antigen recognized by T cells 1 (MART−1) peptide. Additionally, cc−IL-4−DCs produced higher levels of IFN−γ, possessing the CTL induction. Furthermore, DNA microarrays revealed the upregulation of BCL2A1, a pro−survival gene. According to these findings, the cc−IL-4−DCs are useful for generating homogeneous and functional IL-4−DCs that would be expected to promote long−lasting effects in DC vaccines.

Personalized deep learning of individual immunopeptidomes to identify neoantigens for cancer vaccines

Tumour-specific neoantigens play a major role for developing personal vaccines in cancer immunotherapy. We propose a personalized de novo peptide sequencing workflow to identify HLA-I and HLA-II neoantigens directly and solely from mass spectrometry data. Our workflow trains a personal deep learning model on the immunopeptidome of an individual patient and then uses it to predict mutated neoantigens of that patient. This personalized learning and mass spectrometry-based approach enables comprehensive and accurate identification of neoantigens. We applied the workflow to datasets of five patients with melanoma and expanded their predicted immunopeptidomes by 5–15%. Subsequently, we discovered neoantigens of both HLA-I and HLA-II, including those with validated T-cell responses and those that had not been reported in previous studies. Neoantigens play a critical role in cancer immunotherapy. Tran et al. show how training a personalized deep learning model for each individual patient can improve the accuracy and identification rate of mutated neoantigens.

In vivo therapeutic effects of colorectal cancer cell-derived exosomes.

Objective(s):Exosomes are nano-sized structures with lipid bilayer membranes that can be secreted by cancer cells. They play an important role in the biology of the tumor extracellular matrix. Exosomes may contain and transfer tumor antigens to dendritic cells to trigger T cell-mediated anti-tumor immune responses. Materials and Methods:BALB/c mice bearing CT26 colorectal cancer were treated subcutaneously with purified exosomes from analogous tumor cells. The mice were analyzed with respect to tumor size, survival, and anti-tumor immunity responses, including gene expression of cytokines and flowcytometry analysis of T lymphocytes. Results:The rate of tumor size growth in the exosome-treated group significantly decreased (P<0.05), and the flow cytometry results showed a significant reduction in the spleen regulatory T cells (Tregs) count of the exosome-treated group, compared with the untreated group (P=0.02). Although the increase in the serum level of interferon-γ (IFN-γ) and the number of cytotoxic CD8 T lymphocytes (CTLs) in the spleen tissue was not significant (P>0.05), the gene expression of IFN-γ increased significantly (P=0.006). Conclusion:The present results revealed that subcutaneous administration of tumor-derived exosomes could effectively lead to the inhibition of tumor progression by decreasing the number of Treg cells and up-regulation of the IFN-γ gene. Therefore, tumor-derived exosomes can be used as potential vaccines in cancer immunotherapy.

Antigen processing and presentation in cancer immunotherapy.

BackgroundKnowledge about and identification of T cell tumor antigens may inform the development of T cell receptor-engineered adoptive cell transfer or personalized cancer vaccine immunotherapy. Here, we review antigen processing and presentation and discuss limitations in tumor antigen prediction approaches.MethodsOriginal articles covering antigen processing and presentation, epitope discovery, and in silico T cell epitope prediction were reviewed.ResultsNatural processing and presentation of antigens is a complex process that involves proteasomal proteolysis of parental proteins, transportation of digested peptides into the endoplasmic reticulum, loading of peptides onto major histocompatibility complex (MHC) class I molecules, and shuttling of peptide:MHC complexes to the cell surface. A number of T cell tumor antigens have been experimentally validated in patients with cancer. Assessment of predicted MHC class I binding and total score for these validated T cell antigens demonstrated a wide range of values, with nearly one-third of validated antigens carrying an IC50 of greater than 500 nM.ConclusionsAntigen processing and presentation is a complex, multistep process. In silico epitope prediction techniques can be a useful tool, but comprehensive experimental testing and validation on a patient-by-patient basis may be required to reliably identify T cell tumor antigens.

Reader-free ELISPOT assay for immuno-monitoring in peptide-based cancer vaccine immunotherapy.

Cancer vaccine immunotherapy is a therapy that induces cellular immune responses against a target molecule to elicit clinical anti-tumor effects. These cellular immune responses against the target molecule are monitored to evaluate whether the antigen-specific cellular immune responses are induced and maintained during the vaccination period. Enzyme-linked immunospot (ELISPOT) assay is widely performed to analyze not only the frequency of immune cells, but also their effector functions as determined by their cytokine production/secretion. The present study aimed to develop a reader-free ELISPOT assay using a handy membrane-punching device termed ELI 8. With the assistance of particle analysis by ImageJ software, the results of spot counting were reproducible with high inter-assay and inter-examiner concordance. Immune cells that produce and secrete Th1 cytokines without antigen-peptide stimulation of peripheral blood mononuclear cells (PBMCs) were detected, and their frequencies in patients with cancer were significantly higher compared with those in healthy individuals. These frequencies varied between individuals, as well as between time points during the course of cancer vaccine immunotherapy in each patient. Due to the variability in spontaneous cytokine production/secretion by PBMCs, an antigen-specific immune response (IR) index is proposed, which is a ratio of the number of spot-forming cells (SFCs) subjected to antigen-stimulation to that of SFCs with spontaneous cytokine secretion without antigen-stimulation. This index may be used as a marker for antigen-specific cellular immune responses in patients treated with cancer immunotherapy. The IR index successfully detected the induction of Wilms' tumor 1-specific cellular immune responses in patients with cancer treated with cancer vaccine immunotherapy.

Abstract PR14: Emergence of quality metrics for neoantigens: Dissimilarity to the self-proteome as a novel determinant of immunogenicity

Abstract Fewer than 2% of computationally predicted neoantigens are immunogenic, a proven barrier to the efficacy of neoantigen vaccines. Currently, strong MHC affinity is dominant among neoantigen selection criteria for targeted therapies. To enrich for neoantigens with the greatest likelihood of immunogenicity, we developed an analytic method to parse neoantigen quality through rational biologic criteria and applied this method across five clinical datasets for 318 cancer patients. We assessed absolute MHC affinity, pathogen homology, and a novel analysis of dissimilarity to the self-proteome. We hypothesized that sequences with high dissimilarity to wild-type sequences would be more likely to perceived as “non-self” by immunosurveilling T cells. In a validation dataset, dissimilarity enriched for immunogenic peptides with an odds ratio of 34.9 (95% CI: 30.9 to 39.5, p &amp;lt; 0.001). Pathogen homology enriched 3.9-fold (95% CI: 3.6 to 4.3, p &amp;lt; 0.001), whereas selection on the basis of strong MHC-binding affinity alone enriches only 1.4-fold (95% CI: 1.2 to 1.5, p &amp;lt; 0.001). In patient tumors, these newly classified high-dissimilarity neoantigens were rare (1.18% of predicted MHC binders), did not overlap with the other metrics of neoantigen quality, and were enriched for hydrophobic sequences. While conventionally predicted neoantigens did not correlate with survival in two trials of PD-1 checkpoint therapy in patients with non-small cell lung cancer, high-dissimilarity neoantigens, even independent of MHC affinity, were predictive (HR - 3.29, 95% CI: 1.50 – 7.22, p = 0.014 and 3.40, 95% CI: 1.37 – 8.47, p = 0.021). Furthermore, we found that dissimilar peptides were enriched among known immunogenic neoantigens reported in multiple independent settings, including vaccine clinical trials (p = 0.001 – 0.023). This enrichment was not explained by a correlation with reported MHC binding affinities. Dissimilarity also enriched for immunogenicity in a dataset of human autoantigens, tumor-associated antigens, and cancer-testis antigens (odds ratio: 10.44, p &amp;lt; 2.2e-16). Dissimilarity to the self-proteome is therefore an orthogonal approach to MHC affinity for predicting CD8 T cell immunogenicity in both neoantigens and self-antigens. Overall, we show that neoantigen quality, including our novel analysis of dissimilarity to the self-proteome, identifies immunogenic peptides from conventionally predicted neoantigens for which the immunogenic “hit rate” is currently low and facilitates the more rapid development of neoantigen vaccines for cancer immunotherapy. Our pipeline, antigen.garnish, is open source and available on GitHub. This abstract is also being presented as Poster B30. Citation Format: Lee P. Richman, Andrew J. Rech, Robert H. Vonderheide. Emergence of quality metrics for neoantigens: Dissimilarity to the self-proteome as a novel determinant of immunogenicity [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr PR14.

Highly efficient and tumor-selective nanoparticles for dual-targeted immunogene therapy against cancer.

While immunotherapy holds great promise for combating cancer, the limited efficacy due to an immunosuppressive tumor microenvironment and systemic toxicity hinder the broader application of cancer immunotherapy. Here, we report a combinatorial immunotherapy approach that uses a highly efficient and tumor-selective gene carrier to improve anticancer efficacy and circumvent the systemic toxicity. In this study, we engineered tumor-targeted lipid-dendrimer-calcium-phosphate (TT-LDCP) nanoparticles (NPs) with thymine-functionalized dendrimers that exhibit not only enhanced gene delivery capacity but also immune adjuvant properties by activating the stimulator of interferon genes (STING)-cGAS pathway. TT-LDCP NPs delivered siRNA against immune checkpoint ligand PD-L1 and immunostimulatory IL-2-encoding plasmid DNA to hepatocellular carcinoma (HCC), increased tumoral infiltration and activation of CD8+ T cells, augmented the efficacy of cancer vaccine immunotherapy, and suppressed HCC progression. Our work presents nanotechnology-enabled dual delivery of siRNA and plasmid DNA that selectively targets and reprograms the immunosuppressive tumor microenvironment to improve cancer immunotherapy.

Hsp70 in Cancer: Partner or Traitor to Immune System.

Heat shock protein 70.1 (Hsp70.1), also known as Hsp70, is a highly conserved member of the heat shock protein family that exists in all living organisms and determines the protein fate as molecular chaperones. Hsp70 basal expression is undetectable or low in most unstressed normal cells, however, its abundant presence in several types of human cancer cells is reported. Several studies support upregulated Hsp70 involved in tumor progression and drug resistance through modulation of cell death pathways and suppresses anticancer immune responses. However, numerous studies have confirmed that Hsp70 can also induce anticancer immune responses through the activation of immune cells in particular antigen-presenting cells (APCs). Regarding the significant and the promising role of vaccines in cancer immunotherapy, identification and characterization of the overexpressed Hsp70 as a potential immune stimulatory factor can pave the path for development of highly effective anticancer vaccines. In this review, we will discuss the interactions of Hsp70 with components of the immune system in cancers as well as possible strategies to harness Hsp70 for eliciting anticancer immune responses.

A Novel Anti-PD-L1 Vaccine for Cancer Immunotherapy and Immunoprevention.

Dendritic cells (DCs) are potent antigen-presenting cells that play a critical role in activating cellular and humoral immune responses. DC-based tumor vaccines targeting tumor-associated antigens (TAAs) have been extensively tested and demonstrated to be safe and potent in inducing anti-TAA immune responses in cancer patients. Sipuleucel-T (Provenge), a cancer vaccine of autologous DCs loaded with TAA, was approved by the United States Food and Drug Administration (FDA) for the treatment of castration-resistant prostate cancer. Sipuleucel-T prolongs patient survival, but has little or no effect on clinical disease progression or biomarker kinetics. Due to the overall limited clinical efficacy of tumor vaccines, there is a need to enhance their potency. PD-L1 is a key immune checkpoint molecule and is frequently overexpressed on tumor cells to evade antitumor immune destruction. Repeated administrations of PD-L1 or PD-1 antibodies have induced sustained tumor regression in a fraction of cancer patients. In this study, we tested whether vaccinations with DCs, loaded with a PD-L1 immunogen (PDL1-Vax), are able to induce anti-PD-L1 immune responses. We found that DCs loaded with PDL1-Vax induced anti-PD-L1 antibody and T cell responses in immunized mice and that PD-L1-specific CTLs had cytolytic activities against PD-L1+ tumor cells. We demonstrated that vaccination with PDL1-Vax DCs potently inhibited the growth of PD-L1+ tumor cells. In summary, this study demonstrates for the first time the principle and feasibility of DC vaccination (PDL1-Vax) to actively induce anti-PD-L1 antibody and T cell responses capable of inhibiting PD-L1+ tumor growth. This novel anti-PD-L1 vaccination strategy could be used for cancer treatment and prevention.

Co-localized delivery of nanomedicine and nanovaccine augments the postoperative cancer immunotherapy by amplifying T-cell responses

Immunotherapy in solid tumors is limited by the poor immunogenicity of tumors and limited T-cell immune response, resulting in low patient response rate. To increase the efficiency of cancer immunotherapy, a unique synergistic combination cancer immunotherapy by co-localized delivery of cancer nanomedicine for enhancing the tumor immunogenicity and nanovaccine for augmenting the antitumor T-cell immunity was developed for post-surgical tumor treatment. The thermo-responsive, curcumin-loaded polymer nanoparticles (nanomedicine)-assembled hydrogel enabled the complete coverage of the surgical bed of primary tumor and the spatio-temporal delivery of cognate nanomedicines and encapsulated nanovaccines. Importantly, the nanomedicine efficiently induced the immunogenic cell death (ICD) of residual cancer cells, and consequently enhanced the tumor immunogenicity and sensitized the tumor to antitumor T-cell immunity. The cancer nanovaccine composed of antigenic peptide, CpG-ODN and cationic polymer nanoparticle significantly triggered the maturation of dendritic cells (DCs) and elicited potent vaccine-specific T-cell immune responses. Using highly malignant postoperative breast carcinoma 4T1 models, we found that the combination immunotherapy strategy strikingly amplified the level of systemic host T-cell immunity, promoted the infiltration of CD8+ T lymphocytes in tumor, and thus efficaciously attenuated the local tumor recurrence and pulmonary metastasis. Collectively, this work provided an advanced synergistic combination approach for post-surgical tumor immunotherapy. The self-assembled hydrogel should enable a broader combination of immunomodulating nanomedicines and vaccines for cancer immunotherapy.

Delivery of nitric oxide with a nanocarrier promotes tumour vessel normalization and potentiates anti-cancer therapies.

Abnormal tumour vasculature has a significant impact on tumour progression and response to therapy. Nitric oxide (NO) regulates angiogenesis and maintains vascular homeostasis and, thus, can be delivered to normalize tumour vasculature. However, a NO-delivery system with a prolonged half-life and a sustained release mechanism is currently lacking. Here we report the development of NanoNO, a nanoscale carrier that enables sustained NO release to efficiently deliver NO into hepatocellular carcinoma. Low-dose NanoNO normalizes tumour vessels and improves the delivery and effectiveness of chemotherapeutics and tumour necrosis factor-related, apoptosis-inducing, ligand-based therapy in both primary tumours and metastases. Furthermore, low-dose NanoNO reprogrammes the immunosuppressive tumour microenvironment toward an immunostimulatory phenotype, thereby improving the efficacy of cancer vaccine immunotherapy. Our findings demonstrate the ability of nanoscale NO delivery to efficiently reprogramme tumour vasculature and immune microenvironments to overcome resistance to cancer therapy, resulting in a therapeutic benefit.

In Vivo Administration of Recombinant Human Granulocyte Colony-Stimulating Factor Increases the Immune Effectiveness of Dendritic Cell-Based Cancer Vaccination.

Significant recent advances in cancer immunotherapeutics include the vaccination of cancer patients with tumor antigen-associated peptide-pulsed dendritic cells (DCs). DC vaccines with homogeneous, mature, and functional activities are required to achieve effective acquired immunity; however, the yield of autologous monocyte-derived DCs varies in each patient. Priming with a low dose of recombinant human granulocyte colony-stimulating factor (rhG-CSF) 16–18 h prior to apheresis resulted in 50% more harvested monocytes, with a significant increase in the ratio of CD11c+CD80+ DCs/apheresed monocytes. The detection of antigen-specific cytotoxic T lymphocytes after Wilms’ tumor 1-pulsed DC vaccination was higher in patients treated with rhG-CSF than those who were not, based on immune monitoring using tetramer analysis. Our study is the first to report that DC vaccines for cancer immunotherapy primed with low-dose rhG-CSF are expected to achieve higher acquired immunogenicity.

Bacillus Calmette-Guérin (BCG)-Cell Wall Skeleton as Immunotherapeutic Option for BCG-Refractory Superficial Bladder Cancer

Although intravesical instillation of Mycobacterium bovis bacillus Calmette-Guérin (BCG) is the most successful cancer immunotherapy for superficial bladder cancer, the serious side effects are frequently arisen by using live mycobacteria. To allow less toxic and more potent immunotherapeutic agents following intravesical BCG treatment for superficial bladder cancer, noninfectious immunotherapeutic drug instead of live BCG would be highly desirable. Recently, immune-enhancing adjuvants are considered an effective vaccine immunotherapy for cancer, providing enhanced antitumor effects and boosted immunity. The BCG-cell wall skeleton (BCG-CWS), the main immune active center of BCG, is a potent candidate as a noninfectious immunotherapeutic drug instead of live BCG against bladder cancer. However, the most limited application for anticancer therapy, it is difficult to formulate a water- soluble BCG-CWS due to the aggregation of BCG-CWS in both aqueous and nonaqueous solvents. To overcome the insolubility and improve the internalization of BCG-CWS into bladder cancer cells, it should be developed the lipid nanoparticulation of BCG-CWS, resulting in improved dispensability, stability, and small size. In addition, powerful technology of delivery systems should be applied to enhance the internalization of BCG-CWS, such as encapsulated into lipid nanoparticles using novel packaging methods. Here, we describe the progress in research on effects of BCG-CWS for cancer immunotherapy, development of lipid-based solvent, and packaging method using nanoparticles with drug delivery system. Key Words: Bacillus Calmette-Guérin; Cell wall skeleton; Bladder cancer; Adjuvant immunotherapy; Drug delivery system.

Abstract 1464: Inhibition of p38 MAPK in dendritic cells enhances their antigen presentation and induces Th17 T cell differentiation

Abstract Dendritic cells (DCs) are the most potent antigen-presenting cells which bridges innate and adaptive immunity, but how DC-derived signals regulate and induce T cell lineage choices remains unclear. The p38 MAPK pathway plays an essential role in regulating cellular processes such as cell differentiation, growth, and death. In this study, SB203580 was employed to selectively inhibit p38 pathway in bone marrow derived DCs (BMDCs) to investigate the effects of this pathway on the characteristic phenotype and function of DCs, especially the induction on T helper cell differentiation. We found that inhibition of p38 increased the proliferation of BMDCs, but did not alter their phagocytic ability. Also, inhibition of p38 enhanced the activation of BMDCs, as evidenced by the up-regulated expression of DCs-related surface markers including CD80, CD86 and MHCII. However, the secretion levels of IL-12 and IL-10 in BMDCs were reduced significantly, whereas the level of IL-6 was not influenced by the p38 inhibitor. In addition, we immunized the mice with BMDCs vaccines and studied the production of antigen-specific Th17 T cell in spleen. Our data demonstrated that p38-inhibited DCs vaccine could induce more antigen-specific Th17 T cells than regular DCs vaccine in vivo. Collectively, these results support the hypothesis that the p38 pathway plays a critical role in the immunologic activation of DCs. Our findings suggest that inhibition p38 pathway in DCs may be a new strategy for generating potent DC vaccines for cancer immunotherapy. Citation Format: Yan Luo, Shreeder Barath, Deborah A. Bahr, Navnita Dutta, Geraldine Raja, Martin J. Cannon, Keith L. Knutson. Inhibition of p38 MAPK in dendritic cells enhances their antigen presentation and induces Th17 T cell differentiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1464.

Transendothelial migration (TEM) of in vitro generated dendritic cell vaccine in cancer immunotherapy.

Many efforts have been made to improve the efficacy of dendritic cell (DC) vaccines in DC-based cancer immunotherapy. One of these efforts is to deliver a DC vaccine more efficiently to the regional lymph nodes (rLNs) to induce stronger anti-tumor immunity. Together with chemotaxis, transendothelial migration (TEM) is believed to be a critical and indispensable step for DC vaccine migration to the rLNs after administration. However, the mechanism underlying the in vitro-generated DC TEM in DC-based cancer immunotherapy has been largely unknown. Currently, junctional adhesion molecules (JAMs) were found to play an important role in the TEM of in vitro generated DC vaccines. This paper reviews the TEM of DC vaccines and TEM-associated JAM molecules.

Biomimetic Glyconanoparticle Vaccine for Cancer Immunotherapy.

Cancer immunotherapy aims to harness the immune system to combat malignant processes. Transformed cells harbor diverse modifications that lead to formation of neoantigens, including aberrantly expressed cell surface carbohydrates. Targeting tumor-associated carbohydrate antigens (TACA) hold great potential for cancer immunotherapy. N-glycolylneuraminic acid (Neu5Gc) is a dietary non-human immunogenic carbohydrate that accumulates on human cancer cells, thereby generating neoantigens. In mice, passive immunotherapy with anti-Neu5Gc antibodies inhibits growth of Neu5Gc-positive tumors. Here, we designed an active cancer vaccine immunotherapy strategy to target Neu5Gc-positive tumors. We generated biomimetic glyconanoparticles using engineered αGal knockout porcine red blood cells to form nanoghosts (NGs) that either express (NGpos) or lack expression (NGneg) of Neu5Gc-glycoconjugates in their natural context. We demonstrated that optimized immunization of "human-like" Neu5Gc-deficient Cmah-/- mice with NGpos glyconanoparticles induce a strong, diverse and persistent anti-Neu5Gc IgG immune response. The resulting anti-Neu5Gc IgG antibodies were also detected within Neu5Gc-positive tumors and inhibited tumor growth in vivo. Using detailed glycan microarray analysis, we further demonstrate that the kinetics and quality of the immune responses influence the efficacy of the vaccine. These findings reinforce the potential of TACA neoantigens and the dietary non-human sialic acid Neu5Gc, in particular, as immunotherapy targets.

Abstract B100: Development of fargeted multiple myeloma cancer vaccine and antigen-specific T-cell immunotherapy using novel Immunogenic-engineered heteroclitic BCMA peptides

Abstract Background: Multiple myeloma (MM), the second most common hematologic malignancy in the US, is characterized by the proliferation and accumulation of clonal malignant plasma cells in the bone marrow, associated with hypercalcemia, renal dysfunction and bone disease. Despite recent advances in treatment including novel therapeutics in combination with transplantation, MM still remains incurable. We have recently developd a highly immunogenic HLA-A2-specific multipeptide cancer vaccine targeting XBP1 (X-box binding protein 1), CD138 (Syndecan-1) and CS1 (SLAMF7) antigens. In both pre-clinical studies and Phase 1/2a clinical trials in patients with smoldering multiple myeloma and triple negative breast cancer, vaccination with this multi-peptide based cancer vaccine induced antigen-specific and Th1-type anti-tumor immune responses, which were maintained for long-term within tetramer+/memory (CD45RO+) CD8 cytotoxic T lymphocytes (CTL). The immune responses were further enhanced in patients who received vaccination in combination with lenalidomide or checkpoint inhibitor. To allow for vaccination against additional tumor-associated antigens, we have recently investigated B Cell Maturation Antigen (BCMA), a cell surface antigen restricted to MM and normal plasma cells, as well as accessory dendritic cells. As the receptor for binding of B cell activating factor (BAFF) and of a proliferation-inducing ligand (APRIL), BCMA promotes MM cell growth, drug resistance, as well as survival of long lived plasma cells. Due to its restricted expression pattern, targeting of this antigen with antibodies, immunotoxins, and CAR T-cells is already ongoing in MM at present. Objective: We aimed to identify immunogenic BCMA peptides in order to generate antigen-specific CD8+ effector cytotoxic T lymphocytes against MM cells. Findings: We identified novel immunogenic HLA-A2 native and engineered heteroclitic BCMA peptides that induce tumor-specific CTL against MM. The engineered heteroclitic BCMA72-80 and BCMA54-62 peptides have improved HLA-A2 binding affinity and stability compared to their native BCMA72-80 and BCMA54-62 peptides. In preclinical studies, each of the heteroclitic BCMA peptide induced antigen specific CTL, which expressed increased T-cell activation (CD38, CD69) and co-stimulatory (CD40L, OX40, GITR) molecules. The engineered heteroclitic BCMA72-80 triggered a more robust immune response than BCMA54-62 peptide, associated with increased HLA-A2 binding affinity and stability. Importantly, the heteroclitic BCMA72-80 peptide-specific CTL induced selective and robust proliferative and cytolytic activities in response to MM patients’ tumor cells. Specifically, these tetramer+ CD8+ CTL demonstrated HLA-A2-restricted immune responses against MM, associated with CD107a degranulation, proliferation, Th-1 cytokine (IFN-γ/IL-2/TNF-α) cytokine production, perforin/granzyme B up-regulation, and increased 41BB expression. Furthermore, the heteroclitic BCMA72-80 peptide has demonstrated its immunogenicity through development central memory and effector memory CTL, which showed polyfunctional antitumor activities against MM including patients’ primary tumor cells and cell lines. This novel engineered heteroclitic BCMA72-80 peptide may therefore be useful for generation of antigen-specific and tumor-selective CTL in MM. Significance: We have identified BCMA-specific native and engineered heteroclitic peptides which induce BCMA antigen specific CD8+ CTL with robust anti-MM activity. This immunogenic BCMA peptide will be utlized in clinical protocols of vaccination and/or adoptive T-cells immunotherapy to trigger antigen-specific central and effector memory CTL anti-MM immunity. Citation Format: Jooeun Bae, Teru Hideshima, Yu-Tzu Tai, Nikhil Munshi, Kenneth Anderson. Development of fargeted multiple myeloma cancer vaccine and antigen-specific T-cell immunotherapy using novel Immunogenic-engineered heteroclitic BCMA peptides [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B100.

Vaccines for cancer immunotherapy: An evidence-based review on current status and future perspectives

Vaccines for cancer immunotherapy: An evidence-based review on current status and future perspectives

Cancer Vaccine Immunotherapy with RNA-Loaded Liposomes.

Cancer vaccines may be harnessed to incite immunity against poorly immunogenic tumors, however they have failed in therapeutic settings. Poor antigenicity coupled with systemic and intratumoral immune suppression have been significant drawbacks. RNA encoding for tumor associated or specific epitopes can serve as a more immunogenic and expeditious trigger of anti-tumor immunity. RNA stimulates innate immunity through toll like receptor stimulation producing type I interferon, and it mediates potent adaptive responses. Since RNA is inherently unstable, delivery systems have been developed to protect and deliver it to intended targets in vivo. In this review, we discuss liposomes as RNA delivery vehicles and their role as cancer vaccines.

The Journey of in vivo Virus Engineered Dendritic Cells From Bench to Bedside: A Bumpy Road.

Dendritic cells (DCs) are recognized as highly potent antigen-presenting cells that are able to stimulate cytotoxic T lymphocyte (CTL) responses with antitumor activity. Consequently, DCs have been explored as cellular vaccines in cancer immunotherapy. To that end, DCs are modified with tumor antigens to enable presentation of antigen-derived peptides to CTLs. In this review we discuss the use of viral vectors for in situ modification of DCs, focusing on their clinical applications as anticancer vaccines. Among the viral vectors discussed are those derived from viruses belonging to the families of the Poxviridae, Adenoviridae, Retroviridae, Togaviridae, Paramyxoviridae, and Rhabdoviridae. We will further shed light on how the combination of viral vector-based vaccination with T-cell supporting strategies will bring this strategy to the next level.