3,293 research outputs found
Novel players: tissue-resident memory B cells
No full textThe paper by Shlomchik and colleagues in this issue of Blood identifies a novel subset of human memory B cells (MBCs), tissue-resident memory B (BRM) cells, with a unique gene expression signature and a function distinct from conventional CD271 MBCs
HNSCC: tumour antigens and their targeting by immunotherapy
No full textHead and neck squamous cell carcinomas (HNSCC) are a heterogeneous group of malignant tumours typically caused by alcohol and tobacco consumption, although an increasing number of HNSCC arise due to persistent infection with high-risk human papilloma virus (HPV). The treatment of HNSCC remains challenging, and the first-line setting is focused on surgery and chemoradiotherapy. A substantial proportion of HNSCC patients die from their disease, especially those with recurrent and metastatic disease. Among factors linked with good outcome, immune cell infiltration appears to have a major role. HPV-driven HNSCC are often T-cell rich, reflecting the presence of HPV antigens that are immunogenic. Tumour-associated antigens that are shared between patients or that are unique to an individual person may also induce varying degrees of immune response; studying these is important for the understanding of the interaction between the host immune system and the cancer. The resulting knowledge is critical for the design of better immunotherapies. Key questions are: Which antigens lead to an adaptive immune response in the tumour? Which of these are exploitable for immunotherapy? Here, we review the current thinking regarding tumour antigens in HNSCC and what has been learned from early phase clinical trials
DNA fusion vaccines against B-cell tumors
No full textDNA vaccination is currently being explored as a potential strategy for combatting cancer. However, tumor antigens are often weak and the immune system of patients may be compromised. For B-cell tumors, immunoglobulin idiotypic antigens provide defined targets but are poorly immunogenic. Fusion of a sequence derived from tetanus toxin to the genes encoding idiotypic determinants has proved highly effective in activating protective anti-tumor immunity. DNA fusion vaccines containing immuno-enhancing sequences can augment and direct immune attack on a range of target antigens. Gene-based fusion vaccines offer ease of manipulation and flexible design to activate effective attack on cancer
Linked CD4 T cell help: broadening immune attack against cancer by vaccination
No full textIn the last decade, immunotherapy with monoclonal antibodies targeting immunological check points has become a breakthrough therapeutic modality for solid cancers. However, only up to 50 % of patients benefit from this powerful approach. For others vaccination might provide a plausible addition or alternative. For induction of effective anticancer immunity CD4+ T cell help is required, which is often difficult to induce to self cancer targets because of tolerogenic mechanisms. Our approach for cancer vaccines has been to incorporate into the vaccine design sequences able to activate foreign T cell help, through genetically linking cancer targets to microbial sequences (King et al. in Nat Med 4(11):1281–1286, 1998; Savelyeva et al. in Nat Biotechnol 19(8):760–764, 2001). This harnesses the non-tolerized CD4 T cell repertoire available in patients to help induction of effective immunity against fused cancer antigens. Multiple immune effector mechanisms including antibody, CD8+ T cells as well as CD4 effector T cells can be activated using this strategy. Delivery via DNA vaccines has already indicated clinical efficacy. The same principle of linked T cell help has now been transferred to other novel vaccine modalities to further potentiate immunity against cancer targets
High-affinity memory B cells induced by conjugate vaccines against weak tumor antigens are vulnerable to nonconjugated antigen
No full textInduction of antibody-mediated immunity against hematologic malignancies requires CD4+ T-cell help, but weak tumor antigens generally fail to induce adequate T-cell responses, or to overcome tolerance. Conjugate vaccines can harness alternative help to activate responses, but memory B cells may then be exposed to leaking tumor-derived antigen without CD4+ T-cell support. We showed previously using lymphoma-derived idiotypic antigen that exposure to “helpless” antigen silences the majority of memory IgG+ B cells. Transfer experiments now indicate that silencing is permanent. In marked contrast to IgG, most coexisting IgM+ memory B cells exposed to “helpless” antigen survive. Confirmation in a hapten (NP) model allowed measurement of affinity, revealing this, rather than isotype, as the determinant of survival. IgM+ B cells had Ig variable region gene usage similar to IgG but with fewer somatic mutations. Survival of memory B cells appears variably controlled by affinity for antigen, allowing a minority of low affinity IgG+, but most IgM+, memory B cells to escape deletion in the absence of T-cell help. The latter remain, but the majority fail to undergo isotype switch. These findings could apply to other tumor antigens and are relevant for vaccination strategies aimed to induce long-term antibody
Plant viral genes in DNA idiotypic vaccines activate linked CD4+ T-cell mediated immunity against B-cell malignancies
No full textDNA delivery of tumor antigens can activate specific immune attack on cancer cells. However, antigens may be weak, and immune capacity can be compromised. Fusion of genes encoding activating sequences to the tumor antigen sequence facilitates promotion and manipulation of effector pathways. Idiotypic determinants of B-cell tumors, encoded by the variable region genes, are clone-specific tumor antigens. When assembled as single-chain Fv (scFv) alone in a DNA vaccine, immunogenicity is low. Previously, we found that fusion of a sequence from tetanus toxin (fragment C; FrC) promoted anti-idiotypic protection against lymphoma and myeloma. We have now investigated an alternative fusion gene derived from a plant virus, potato virus X coat protein, a primary antigen in humans. When fused to scFv, the self-aggregating protein generates protection against lymphoma and myeloma. In contrast to scFv?FrC, protection against lymphoma is mediated by CD4+ T cells, as is protection against myeloma. Plant viral proteins offer new opportunities to activate immunity against linked T-cell epitopes to attack cancer
Inhibition of a vaccine-induced anti-tumor B cell response by soluble protein antigen in the absence of continuing T cell help
No full textDNA vaccination can elicit the production of anti-tumor antibodies, thus obviating the need to continuously administer passive antibody. This vaccination strategy is particularly important where antibodies have proven to be effective anti-tumor agents. To amplify antibody responses against weak tumor antigens, we previously designed DNA-fusion vaccines incorporating tumor sequences linked to microbial genes. By using a safe idiotypic (Id) antigen from a B cell tumor fused to a fragment C (FrC) sequence from tetanus toxin, we induced both anti-Id and anti-FrC antibodies. It was important to determine whether the antigen itself, either injected or released from residual tumor cells, would boost the antibody response. Id protein not only failed to boost the response, but permanently and rapidly inhibited it by ablating Id-specific memory B cells. In contrast, an Id protein-FrC conjugate boosted both Id-specific and FrC-specific responses. Strikingly, the depletion of CD4+ T cells converted the Id protein-FrC conjugate vaccine into an inhibitor. These findings support the hypothesis that the activation of memory B cells by a DNA vaccine encoding a protein antigen, in the presence of the protein itself, depends completely on T cell help. Furthermore, by using knockout mice, we have shown that inhibition of the Id-specific memory B cells by the Id protein is largely independent of the Fc{gamma}RIIB and, hence, independent of immune complexes. The principles revealed by using a DNA vaccine have implications for all cancer vaccines designed to induce and maintain antibody responses against weak autologous tumor antigens
Cellular immune response - bystander stimulation of activated CD4+ T cells of unrelated specificity following a booster vaccination with tetanus toxoid
No full textAntigen-specific CD4+ T cells are central to natural and vaccine-induced immunity. However an ongoing antigen-specific T-cell response can influence surrounding T cells with unrelated antigen specificities. We previously observed this bystander effect in healthy human subjects following recall vaccination with tetanus toxoid (TT). Since this interplay could be important for maintenance of memory, we have moved to a mouse model for further analysis. We investigated if boosting memory CD4+ T cells against TT in vivo would influence injected CD4+ TCR transgenic T cells (OT-II) specific for an unrelated ovalbumin (OVA) peptide (OVAp). We found that, if OT-II cells were pre-activated with OVAp in vitro,they showed a bystander proliferative response during the ongoing parallel TT-specific response. Bystander proliferation was dependent on boosting of the TT-specific memory response in the recipients, with no effect in naïve mice. Bystander stimulation was also proportional to the strength of the TT-specific memory T-cell response. T cells activated in vitro displayed functional receptors for IL-2 and IL-7, suggesting these as potential mediators. This cross-talk between a stimulated CD4+ memory T-cell response and CD4+ T cells activated by an unrelated antigen could be important in human subjects continually buffeted by environmental antigen
Targeting head and neck cancer by vaccination
No full textHead and neck cancer (HNC) is a heterogeneous group of squamous cell cancers that affect the oral cavity, pharynx, and larynx. Worldwide, it is the sixth most common cancer but in parts of Southern and South-East Asia, HNC is one of the most common cancers. A significant proportion of HNC is driven by human papillomavirus (HPV) infection, whereas HPV-independent HNC is associated with alcohol, smoking, and smokeless tobacco consumption. Here, we review the past and present experience of targeting HNC with vaccination focusing on HPV-derived antigens as well as non-viral antigens for HPV-negative HNC. Novel therapeutic approaches for HNC will focus not only on effective vaccine platforms but will also target the stroma-rich immunosuppressive microenvironment found in those tumours
DNA fusion vaccine designs to induce tumor-lytic CD8+ T-cell attack via the immunodominant cysteine-containing epitope of NY-ESO 1
No full textThe cancer/testis antigen NY-ESO-1 contains an immunodominant HLA-A2-binding peptide (SLLMWITQC), designated S9C, an attractive target for vaccination against several human cancers. As cysteine contains a reactive ?SH, the oxidation status of exogenous synthetic peptide is uncertain. We have designed tolerance-breaking DNA fusion vaccines incorporating a domain of tetanus toxin fused to tumor-derived peptide sequences (p.DOM-peptide), placed at the C-terminus for optimal immunogenicity. In a "humanized" HLA-A2 preclinical model, p.DOM-S9C primed S9C-specific CD8+ T cells more effectively than adjuvanted synthetic peptide. A DNA vaccine encoding the full NY-ESO-1 sequence alone induced only weak S9C-specific responses, amplified by addition of DOM sequence. The analog peptide (SLLMWITQL) also primed peptide-specific CD8+ T cells, again increased by DNA delivery. Importantly, T cells induced by S9C-encoding DNA vaccines killed tumor cells expressing endogenous NY-ESO-1. Only a fraction of T cells induced by the S9L-encoding DNA vaccines was able to recognize S9C and kill tumor cells. These data indicate that DNA vaccines mimic posttranslational modifications of ?SH-containing peptides expressed by tumor cells. Instability of synthetic peptides and the potential dangers of analog peptides contrast with the ability of DNA vaccines to induce high levels of tumor-lytic peptide-specific CD8+ T cells. These findings encourage clinical exploration of this vaccine strategy to target NY-ESO-
- …
