ABSTRACT
Project objective: Despite the recent revolution in immune checkpoint inhibitors (ICIs), only modest improvement in overall survival and likely caused by not enough potent cellular immunity among BC patients. Our lab has been focus on inducing cellular immunity against HER2+ BC through vaccination against the tumor-associated antigen HER2. Approximately 20 years ago, we performed an experimental pilot study by administrating HER2 peptide and recombinant protein pulsed dendritic cells (DC vaccine) to six patients with refractory HER2+ advanced or metastatic (stage II (>= 6 +LN), III, or stage IV) BC. We followed the patients on 2019 found that all of the six patients were still alive, 18 years after vaccination. Their blood sample were analyzed with cytometry by time-offlight (CyTOF) and found there is a significantly increased presence of CD27 expressing memory T cells in response to HER2 peptide stimulation. Recent report on the SARS-CoV2 mRNA vaccine also suggested that CD27 expressing memory T cells plays a critical role in long-lasting cellular immunity against SARS-CoV2 infection. Therefore, we hypothesized that CD27 plays a critical role in cellular immunity against BC, and the stimulation of CD27 expressing T cells with mAb targeting CD27 significantly increase the cellular immunity triggered by vaccination against tumor-associated antigen. Result(s): We recapitulate the rise of CD27+ antigen specific T cells among the vaccinated patients using a transgenic mouse model expressing human CD27. When combined the adenoviral-vector based HER2 (Ad-HER2) vaccination with a single dose of human aCD27 antibody (Varlilumab), we found there is a robust increase in the HER2 specific T cells compared to vaccination alone, especially CD27+CD44+ memory CD4 T cells, even after 120 days post vaccination. Using an ICIinsensitive syngeneic HER2+ BC models, we found 50% of mice in the combination group of aCD27 antibody plus Ad-HER2 showed total tumor regression by the end of study. When combined with anti-PD1 antibody, the combination of AdHER2 and Varlilumab leads to total tumor regression in 90% of tumor bearing mice with syngeneic HER2+ BC, indicating that the vaccination against tumor associated antigen HER2 plus anti-CD27 antibody sensitized ICI-insensitive HER2+ BC toward ICI. Conclusion(s): Our data demonstrates that the administration of anti-CD27 antibody significantly increase the long term presence of CD27+ antigen specific memory T cells after vaccination against tumor associated antigen HER2. As consequence, combination of anti-CD27 with HER2 sensitized the immune unresponsive breast cancer toward anti-PD1 antibody. Our study suggests that the vaccination against tumor-associated antigen with mAb targeting CD27 leads to the robust cellular immunity, which is required for successful ICIs against breast cancer.
ABSTRACT
Background: Following natural infection or vaccination, the generation of stem cell-like memory T (Tscm) cells is essential for long-term protective immunity to the virus. Tscm cells have the capacity for self-renewal and multipotency. In SARS-CoV2 infection, the emergence of CD8+ Tscm cells is correlated with the number of symptom-free days. The development of a COVID-19 vaccine able to generate CD8+ Tscm cells is of the utmost importance since the emergence of SARS-CoV2 variants of concerns requires maintaining strong and long-lasting immune responses, 2) as an efficient alternative in immunocompromised people who have difficulties raising humoral immune responses. Methods: We have developed a new Dendritic Cell-based vaccine composed of a humanized αCD40 monoclonal antibody fused to the RBD protein in its C-terminal Fc-domains and three T cell epitopes spanning sequences from S and N proteins in its light chains (αCD40-CoV2). Previous studies have shown that this platform elicited durable and robust T-and B-cell responses and is currently in phase I clinical development in HIV. We tested the capacity of two injections of the vaccine (10υg, i.p) given with or without poly(IC) (50υg, i.p) at 3 weeks apart to i) elicit human (hu) B-, and huT-cell responses in NSG mice reconstituted with a Human Immune System (HIS mice), ii) protect against SARS-CoV2 infection in the hCD40xK18hACE2 transgenic mice. Results: We performed AIM assays and intracellular staining on spleen cells of HIS mice stimulated with overlapping peptide pools spanning the sequences of vaccine antigens. We found that both non-adjuvanted and adjuvanted vaccine efficiently induced SARS-CoV2-specific Th1 huCD4+ and huCD8+ T cells in all vaccinees compared to mock animals. SARS-CoV2-specific huCD4+ T cells were polyfunctional. We confirmed the presence of RBD-specific huCD8+ T cells in the vaccinated animals using HLA-I tetramers. A significant proportion of the multimer+ huCD8+ T cells were Tscm (CD45RA+ CD62L+ CD95+) cells in both vaccinated groups. Besides, we detected significant amounts of spike-IgG+ switched huB cells in all vaccinees. In SARS-CoV2 challenge experiments, we further showed that both vaccination settings significantly protected animals with a survival rate of 100%. Conclusion: We demonstrate that the targeting of SARS-CoV-2 epitopes to CD40 induces significant B and T cells with a long-term memory phenotype in HIS mice and the ability of the vaccine to ensure complete protection against SARS-CoV2 infection.
ABSTRACT
Immunotherapy is the newest approach to combat cancer. It can be achieved using several strategies, among which is the dendritic cell (DC) vaccine therapy. Several clinical trials are ongoing using DC vaccine therapy either as a sole agent or in combination with other interventions to tackle different types of cancer. Immunotherapy can offer a potential treatment to coronavirus disease 2019 (COVID-19) the worst pandemic facing this generation, a disease with deleterious effects on the health and economic systems worldwide. We hypothesize that DC vaccine therapy may provide a potential treatment strategy to help combat COVID-19. Cancer patients are at the top of the vulnerable population owing to their immune-compromised status. In this review, we discuss DC vaccine therapy in the light of the body's immunity, cancer, and newly emerging infections such as COVID-19 in hopes of better-customized treatment options for patients with multiple comorbidities.