scholarly journals 759 Development of an implantable artificial lymph node as a therapeutic cancer vaccine

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A807-A807
Author(s):  
Dixita Viswanath ◽  
Hsuan-Chen Liu ◽  
Corrine Ying Xuan Chua ◽  
Alessandro Grattoni
Keyword(s):  
T Cell ◽  
Cancer Vaccine ◽  
Cancer Vaccines ◽  
Antitumor Immunity ◽  
Tumor Antigens ◽  
Clinical Translation ◽  
Laboratory Animals ◽  
Host Immune System ◽  
Cancer Type ◽  
Therapeutic Cancer Vaccine

BackgroundPersonalized therapeutic cancer vaccines aim to target and reprogram the host immune system to achieve cancer eradication in situ. Cancer vaccines deliver two main components: immunostimulants (iS) and tumor antigens to reduce tumor burden with a robust T cell response; however, none have reached broad clinical success due to difficulty in vaccine administration, ex vivo cellular manipulation, low clinical efficacy and broad administrative barriers. While most efforts to date have focused on repeated bolus administrations, biomaterial-based vaccine strategies have led to promising clinical translation.MethodsIn light of these challenges, we have designed a clinically-viable platform-based vaccine strategy, termed the NanoLymph, to provide spatiotemporal elution of immunostimulants and tumor antigens locally to recruit and activate antitumor immunity for cancer eradication. Here, we aim to target the release of granulocyte macrophage colony stimulating factor (GM-CSF) and TLR-7/8 agonist Resiquimod (R848) to promote recruitment and activation of dendritic cells (DCs), a key player in antitumor cytotoxicity.ResultsWe demonstrate the NanoLymph as an structurally stable and biocompatible immunostimulatory niche for durable DC-driven tumor specific T-cell mediated cytotoxicity. Additionally, we demonstrate the NanoLymph’s ability to recruit and activate immune cells of interest, activating antitumor immunity against model antigen. Thus, we have provided the framework necessary to develop a personalized therapeutic cancer vaccine for tumor-specific T-cell mediated responses necessary to generate immunological memory.ConclusionsFuture studies will evaluate immunostimulant and tumor antigen biodistribution in vivo and further apply the NanoLymph in a tumor bearing model to effect antitumor cytotoxicity. Ultimately, we aim to develop a personalized platform applicable for every patient of any cancer type aimed at direct clinical translation.Ethics ApprovalThis study was approved by the Houston Methodist Research Institute (HMRI), according to protocols approved by the Institutional Animal Care and Use Committee (IACUC). HMRI’s Animal Welfare Assurance number is A4555-01. HMRI assures strict compliance with all federal regulations and guidelines involving the use of laboratory animals in biomedical research.

scholarly journals Selecting Target Antigens for Cancer Vaccine Development

Vaccines ◽  
2020 ◽  
Vol 8 (4) ◽  
pp. 615 ◽  
Author(s):  
Luigi Buonaguro ◽  
Maria Tagliamonte
Keyword(s):  
T Cell ◽  
Cancer Vaccine ◽  
Cancer Vaccines ◽  
Tumor Antigens ◽  
Vaccine Development ◽  
T Cell Response ◽  
Therapeutic Cancer Vaccine ◽  
Memory T Cell ◽  
Heteroclitic Peptides ◽  
Therapeutic Cancer Vaccines

One of the principal goals of cancer immunotherapy is the development of efficient therapeutic cancer vaccines that are able to elicit an effector as well as memory T cell response specific to tumor antigens. In recent years, the attention has been focused on the personalization of cancer vaccines. However, the efficacy of therapeutic cancer vaccines is still disappointing despite the large number of vaccine strategies targeting different tumors that have been evaluated in recent years. While the preclinical data have frequently shown encouraging results, clinical trials have not provided satisfactory data to date. The main reason for such failures is the complexity of identifying specific target tumor antigens that should be unique or overexpressed only by the tumor cells compared to normal cells. Most of the tumor antigens included in cancer vaccines are non-mutated overexpressed self-antigens, eliciting mainly T cells with low-affinity T cell receptors (TCR) unable to mediate an effective anti-tumor response. In this review, the target tumor antigens employed in recent years in the development of therapeutic cancer vaccine strategies are described, along with potential new classes of tumor antigens such as the human endogenous retroviral elements (HERVs), unconventional antigens, and/or heteroclitic peptides.

scholarly journals Cancer Vaccine in Solid Tumors: Where We Stand

2021 ◽  
Vol 42 (04) ◽  
pp. 319-324
Author(s):  
Somnath Roy ◽  
Joydeep Ghosh ◽  
Ranti Ghosh
Keyword(s):  
Cancer Vaccine ◽  
Cancer Vaccines ◽  
Tumor Antigens ◽  
Viral Vector ◽  
Target Selection ◽  
Immune Memory ◽  
Therapeutic Cancer Vaccine ◽  
Specific Antigens ◽  
Preclinical And Clinical Studies ◽  
Therapeutic Cancer Vaccines

AbstractCancer immunotherapy has achieved landmark progress in the field of medical oncology in the era of personalized medicine. In the recent past, our knowledge has expanded regarding how tumor cells escape from the immune system, introducing immunosuppressive microenvironments, and developing tolerance. Therapeutic cancer vaccine leads to activation of immune memory that is long-lasting, safe, and effective; hence, it is becoming an attractive method of immunotherapy. Various cancer vaccine trials in the past have taught us the types of target selection, magnitude of immune response, and implementation of appropriate technologies for the development of new successful cancer vaccines. Tumor-associated antigens, cancer germline antigens, oncogenic viral antigens, and tumor-specific antigens, also known as neoantigens, are potential targets for designing therapeutic cancer vaccines. Cancer vaccine could be cell based, viral vector based, peptide based, and nucleic acid based (DNA/RNA). Several preclinical and clinical studies have demonstrated the mechanism of action, safety, efficacy, and toxicities of various types of cancer vaccines. In this article, we review the types of various tumor antigens and types of cancer vaccines tested in clinical trials and discuss the application and importance of this approach toward precision medicine in the field of immuno-oncology.

scholarly journals Cancer Vaccines: Promising Therapeutics or an Unattainable Dream

Vaccines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 668
Author(s):  
Howard Donninger ◽  
Chi Li ◽  
John W. Eaton ◽  
Kavitha Yaddanapudi
Keyword(s):  
Stem Cell ◽  
Immune System ◽  
Tumor Immunity ◽  
Cancer Vaccines ◽  
Tumor Antigens ◽  
Host Immune System ◽  
Tumor Type ◽  
Therapeutic Vaccines ◽  
Cancer Types ◽  
Prophylactic Vaccines

The advent of cancer immunotherapy has revolutionized the field of cancer treatment and offers cancer patients new hope. Although this therapy has proved highly successful for some patients, its efficacy is not all encompassing and several cancer types do not respond. Cancer vaccines offer an alternate approach to promote anti-tumor immunity that differ in their mode of action from antibody-based therapies. Cancer vaccines serve to balance the equilibrium of the crosstalk between the tumor cells and the host immune system. Recent advances in understanding the nature of tumor-mediated tolerogenicity and antigen presentation has aided in the identification of tumor antigens that have the potential to enhance anti-tumor immunity. Cancer vaccines can either be prophylactic (preventative) or therapeutic (curative). An exciting option for therapeutic vaccines is the emergence of personalized vaccines, which are tailor-made and specific for tumor type and individual patient. This review summarizes the current standing of the most promising vaccine strategies with respect to their development and clinical efficacy. We also discuss prospects for future development of stem cell-based prophylactic vaccines.

scholarly journals T cell suppressors of antitumor immunity. The production of Ly-1-,2+ suppressors of delayed sensitivity precedes the production of suppressors of protective immunity.

1986 ◽  
Vol 164 (4) ◽  
pp. 1179-1192 ◽  
Author(s):  
A DiGiacomo ◽  
R J North
Keyword(s):  
T Cell ◽  
Tumor Growth ◽  
Antitumor Immunity ◽  
Tumor Antigens ◽  
Suppressor Cell ◽  
Passive Transfer ◽  
Concomitant Immunity ◽  
Adoptive Immunity ◽  
Suppressor T Lymphocytes ◽  
Early Tumor

The results of this study show that during growth of the immunogenic Meth A fibrosarcoma, two different types of suppressor T lymphocytes are generated in sequence. One type is generated during early tumor growth, reaches peak number around day 6, and is progressively lost thereafter. It is defined by its ability, upon passive transfer, to suppress the expression of a DTH reaction to tumor antigens in tumor-immunized recipients. It bears the Ly1-,2+ membrane phenotype and is sensitive to relatively low doses of cyclophosphamide. In contrast, the second type of suppressor cell is not detected until after day 9 of tumor growth, and is defined by its ability to inhibit, upon passive transfer, the expression of adoptive immunity against an established tumor in T cell-deficient recipients. According to previous studies it bears the Ly1+,2-, L3T4a+ membrane phenotype and is less sensitive to cyclophosphamide than the T cell suppressor of DTH. It is argued that this second type of suppressor T cell seems likely to be responsible for the escape of immunogenic tumors from antitumor immunity, because it can suppress the expression of a powerful mechanism of antitumor immunity in recipient mice, and is generated progressively as the tumor-bearing host loses concomitant immunity. In contrast, although the Ly-1-,2+ T cell suppressors of DTH can efficiently suppress a DTH reaction to an implant of living tumor cells, they fail to suppress the expression of immunity to the same implant.

scholarly journals In Silico Epitope Prediction Analyses Highlight the Potential for Distracting Antigen Immunodominance with Allogeneic Cancer Vaccines

2021 ◽  
Vol 1 (2) ◽  
pp. 115-126
Author(s):  
C. Alston James ◽  
Peter Ronning ◽  
Darren Cullinan ◽  
Kelsy C. Cotto ◽  
Erica K. Barnell ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Vaccine ◽  
Cancer Vaccines ◽  
Cancer Cell Lines ◽  
The Cancer Genome Atlas ◽  
Hla Typing ◽  
Vaccine Antigen ◽  
Cancer Type

Allogeneic cancer vaccines are designed to induce antitumor immune responses with the goal of impacting tumor growth. Typical allogeneic cancer vaccines are produced by expansion of established cancer cell lines, transfection with vectors encoding immunostimulatory cytokines, and lethal irradiation. More than 100 clinical trials have investigated the clinical benefit of allogeneic cancer vaccines in various cancer types. Results show limited therapeutic benefit in clinical trials and currently there are no FDA-approved allogeneic cancer vaccines. We used recently developed bioinformatics tools including the pVACseq suite of software tools to analyze DNA/RNA-sequencing data from the The Cancer Genome Atlas to examine the repertoire of antigens presented by a typical allogeneic cancer vaccine, and to simulate allogeneic cancer vaccine clinical trials. Specifically, for each simulated clinical trial, we modeled the repertoire of antigens presented by allogeneic cancer vaccines consisting of three hypothetical cancer cell lines to 30 patients with the same cancer type. Simulations were repeated ten times for each cancer type. Each tumor sample in the vaccine and the vaccine recipient was subjected to human leukocyte antigen (HLA) typing, differential expression analyses for tumor-associated antigens (TAA), germline variant calling, and neoantigen prediction. These analyses provided a robust, quantitative comparison between potentially beneficial TAAs and neoantigens versus distracting antigens present in the allogeneic cancer vaccines. We observe that distracting antigens greatly outnumber shared TAAs and neoantigens, providing one potential explanation for the lack of observed responses to allogeneic cancer vaccines. This analysis provides additional rationale for the redirection of efforts toward a personalized cancer vaccine approach. Significance: A comprehensive examination of allogeneic cancer vaccine antigen repertoire using large-scale genomics datasets highlights the large number of distracting antigens and argues for more personalized approaches to immunotherapy that leverage recent strategies in tumor antigen identification.

scholarly journals PD-1 Immune Checkpoint Blockade Promotes Therapeutic Cancer Vaccine to Eradicate Lung Cancer

Vaccines ◽  
2020 ◽  
Vol 8 (2) ◽  
pp. 317 ◽  
Author(s):  
Pournima Kadam ◽  
Sherven Sharma
Keyword(s):  
Lung Cancer ◽  
T Cell ◽  
Immune Responses ◽  
Cancer Vaccine ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Tumor Burden ◽  
Tumor Lysate ◽  
Therapeutic Cancer Vaccine ◽  
Tumor Eradication

(1) Background: Targeting inhibitory immune checkpoint molecules has highlighted the need to find approaches enabling the activation of immune responses against cancer. Therapeutic vaccination, which induces specific immune responses against tumor antigens (Ags), is an attractive option. (2) Methods: Utilizing a K-RasG12Dp53null murine lung cancer model we determined tumor burden, tumor-infiltrating T cell (TIL) cytolysis, immunohistochemistry, flow cytometry, and CD4 and CD8 depletion to evaluate the efficacy of PD-1 blockade combined with CCL21-DC tumor lysate vaccine. (3) Results: Anti-PD-1 plus CCL21-DC tumor lysate vaccine administered to mice bearing established tumors (150 mm3) increased expression of perforin and granzyme B in the tumor microenvironment (TME), increased tumor-infiltrating T cell (TIL) activity, and caused 80% tumor eradication. Mice with treatment-induced tumor eradication developed immunological memory, enabling tumor rejection upon challenge and cancer-recurrence-free survival. The depletion of CD4 or CD8 abrogated the antitumor activity of combined therapy. PD-1 blockade or CCL21-DC tumor lysate vaccine monotherapy reduced tumor burden without tumor eradication. (4) Conclusion: Immune checkpoint blockade promotes the activity of the therapeutic cancer vaccine. PD-1 blockade plus CCL21-DC tumor lysate vaccine therapy could benefit lung cancer patients.

A randomized phase II clinical trial of enzalutamide in combination with the therapeutic cancer vaccine, PSA tricom, in metastatic, castration resistant prostate cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS5104-TPS5104
Author(s):  
Nishith K. Singh ◽  
Joseph W. Kim ◽  
Christopher Ryan Heery ◽  
William L. Dahut ◽  
Anna Couvillon ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
T Cells ◽  
T Cell ◽  
Cancer Vaccine ◽  
Phase Iii ◽  
Cytotoxic T Cell ◽  
Phase 2 ◽  
Therapeutic Cancer Vaccine ◽  
Randomized Phase 2

TPS5104 Background: There is a strong rationale to combine therapeutic cancer vaccines with hormonal abrogation in prostate cancer. Androgen abrogation augments T-cell trafficking to prostate, decreases immune tolerance, increases production of naïve thymic T-cells, enhances cytotoxic T-cell repertoire. PSA TRICOM (PROSTVAC) is a therapeutic, viral-vector based, off-the-shelf, cancer vaccine of PSA & 3 co-stimulatory molecules in phase III testing. This was developed at the NCI in collaboration with Bavarian Nordic Immunotherapeutics. It has demonstrated safety and survival benefit in a randomized phase 2 trial of metastatic castrate resistant prostate cancer (mCRPC). Enzalutamide is a modern androgen receptor inhibitor (ARI) approved for the treatment of mCRPC. Data from the clinical trials with these therapies suggest good individual tolerability without any overlapping toxicities. Analysis of previous trials suggests that vaccines may enhance clinical outcomes with ARI. These data form the scientific basis for a combination approach of a cancer vaccine with ARI to control tumor progression in mCRPC. Methods: A randomized, phase 2, open-label clinical trial at the NCI will enroll 72 chemo-naïve, minimally symptomatic patients with mCRPC. They will be randomized (1:1) to enzalutamide (160 mg daily) alone, or enzalutamide with PSA TRICOM for treatment until radiographic progression. PSA-TRICOM will be administered in a core phase (with day 1, 15 and 29 then 4 additional monthly boosts) followed by continued boosts every 3 months. The primary end point will evaluate time to progression in each arm with secondary endpoints including overall survival and systemic immune responses (lymphocyte subsets, regulatory T-cells, regulatory T-cell function, cytokines, naïve thymic emigrants). If a therapeutic cancer vaccine can enhance the clinical efficacy of a hormonal agent such as enzalutamide, it may help define a new role for vaccines as an adjuvant to standard therapies. We will also evaluate this combination in a second trial in non-metastatic, castration-sensitive patients where this combination may yield its greatest clinical impact.

scholarly journals Monitoring T Cells Responses Mounted by Therapeutic Cancer Vaccines

2021 ◽  
Vol 8 ◽  
Author(s):  
Kue Peng Lim ◽  
Nur Syafinaz Zainal
Keyword(s):  
Clinical Trials ◽  
T Cells ◽  
T Cell ◽  
Cancer Vaccine ◽  
Cancer Vaccines ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Rapid Development ◽  
Activated T Cells ◽  
Specific Cytotoxicity

With the regulatory approval of Provenge and Talimogene laherparepvec (T-VEC) for the treatment of metastatic prostate cancer and advanced melanoma respectively, and other promising clinical trials outcomes, cancer vaccine is gaining prominence as a cancer therapeutic agent. Cancer vaccine works to induce T cell priming, expansion, and infiltration resulting in antigen-specific cytotoxicity. Such an approach that can drive cytotoxicity within the tumor could complement the success of checkpoint inhibitors as tumors shown to have high immune cell infiltration are those that would respond well to these antibodies. With the advancements in cancer vaccine, methods to monitor and understand how cancer vaccines modify the immune milieu is under rapid development. This includes using ELISpot and intracellular staining to detect cytokine secretion by activated T cells; tetramer and CyTOF to quantitate the level of antigen specific T cells; proliferation and cell killing assay to detect the expansion of T cell and specific killing activity. More recently, T cell profiling has provided unprecedented detail on immune cell subsets and providing clues to the mechanism involved in immune activation. Here, we reviewed cancer vaccines currently in clinical trials and highlight available techniques in monitoring the clinical response in patients.

Flagellin enhances tumor-specific CD8+ T cell immune responses through TLR5 stimulation in a therapeutic cancer vaccine model

Vaccine ◽  
2013 ◽  
Vol 31 (37) ◽  
pp. 3879-3887 ◽  
Author(s):  
Chung Truong Nguyen ◽  
Seol Hee Hong ◽  
Jeong-Im Sin ◽  
Hong Van Dinh Vu ◽  
Kwangjoon Jeong ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Cancer Vaccine ◽  
Cd8 T Cell ◽  
Therapeutic Cancer Vaccine ◽  
T Cell Immune Responses

An alternative clinical trial design for early cancer vaccine development to phase 3+3 design.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2578-2578
Author(s):  
Emily Gammoh ◽  
Osama E. Rahma ◽  
Richard Simon ◽  
Samir Khleif
Keyword(s):  
Clinical Trial ◽  
Immune Response ◽  
Early Development ◽  
Phase Ii ◽  
Cancer Vaccine ◽  
Dose Escalation ◽  
Cancer Vaccines ◽  
Therapeutic Cancer Vaccine ◽  
Alternative Design ◽  
Immune Modulator

2578 Background: Traditional phase I, “3+3 dose escalation” design, is conducted to identify the MTD and in some cases the optimal biologic dose. Given their unique mechanism of action and the profile of their clinical outcome, this design may not apply to cancer vaccines. The therapeutic cancer vaccine FDA guidance calls for an alternative early development design. Nevertheless, whether an alternative design should be based on “dose escalation” is still an opened question. Methods: We analyzed the toxicity profile in 241 phase 1, 1/2 and pilot therapeutic cancer vaccine trials conducted between 1990 and 2011. Results: Sixty-two grade 3/4 vaccine related systemic toxicities were reported in 4952 treated patients (1.25 events/100 patients). Interestingly, only 2 out of 127 trials that used dose escalation reported vaccine related DLTs, both trials used bacterial vectors. Furthermore, correlation of immunological response with dose level showed no consistent trend. Conclusions: Our analysis suggests that in cancer vaccines neither toxicity nor cellular immune response correlates with dose levels. Accordingly, dose escalation is not suitable for most cancer vaccine studies. Here, we propose a two-step alternative design for early development of cancer vaccines. The first step is to determine and confirm the minimum Immune-Active Dose (IAD). If a vaccine class has been used in humans, IAD dose is chosen based on previous experience if the class is non-toxic (eg. Peptide), otherwise, a traditional dose escalation will be used. For a vaccine class that has not been tested or has undetermined toxicity we recommend “One Patient Escalation Design” (OPSD): one patient is treated per tested dose until an immune response is induced. To confirm this activity, an expanded cohort of 7 patients will be tested until demonstrating an additional response. This will then be used in phase II combination therapy trial. Alternatively, IAD can be directly tested in combination with an immune modulator in a phase II clinical trial using a two-stage design. The first stage of the phase 2 trial can be set at 4-5 patients for a target response rate of over 50%. If no response is seen, then the immune modulator will be escalated in the second stage.

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