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Cancer immune therapy is now used routinely for the treatment of several solid malignancies, albeit just recently having entered the clinic for treatment of haematological malignancies. Several studies demonstrate that cancer immune therapy is a promising treatment modality for the latter. Especially treatment with chimeric antigen receptor T cells for acute lymphoblastic leukaemia and lymphoma is promising. Other promising treatment modalities are immune check point inhibitors for both lymphoid and myeloid malignancies, as well as therapeutic cancer vaccination targeting tumour antigens.

Immunotherapy has played an important part in improving the life of patients with lymphoproliferative diseases especially since the addition of rituximab to chemotherapy in the CD20-positive neoplasms in the 1990s. While this field of passive immunotherapy is continuously evolving, several breakthroughs will expand the treatment modalities to include more active immunotherapy. With the approval of immune checkpoint-blocking antibodies for Hodgkin lymphoma and bispecific antibodies for acute lymphoblastic leukemia (ALL), activation of endogenous T cells already plays a role in several lymphoid malignancies. With the approval of cellular therapies with CAR-T cells for ALL and diffuse large B cell lymphoma, the impact of the manipulation of immune responses is taken even further. Vaccines are cellular therapies in the opposite end of the spectrum in terms of side effects, and while the big breakthrough is still to come, the prospect of a very low-toxic immunotherapy which could be applicable also in premalignant states or in frail patients drives a considerable research activity in the area. In this review, we summarize the mechanisms of action and clinical data on trials in the lymphoid neoplasms with chimeric antigen receptor T cells, bispecific antibodies, immune checkpoint-blocking antibodies, and antineoplastic vaccination therapy.

Historically, the development of cancer vaccines has focused on the central role of tumor antigens in eliciting tumor-specific immune responses, with limited success. Recent advances with checkpoint blockade approaches have brought about a renewed appreciation of the importance of targeting immune suppression in cancer patients. Here we discuss a novel approach to cancer immunotherapy, namely to target recently described T cells that uniquely control cells with immune suppressive functions. Accumulating evidence support the existence of self-reactive T cells that are specific to antigens derived from immunoregulatory proteins ("immunoregulatory antigens"), such as indoleamine 2,3-dioxygenase (IDO) and PD-L1. Vaccination approaches to potentiate these T cells have proven safe with minimal toxicity in the clinical phase I trials conducted thus far. Given that immunoregulatory antigens can be new targets for cancer immunotherapy, we propose here that they could be considered as a new class of tumor antigens. Targeting such antigens has advantages over targeting classical tumor antigens, as there is no requirement for identification of relevant antigens that are specific for the cancer type, and the targets are genetically stable. Furthermore, targeting immunoregulatory antigen-specific T cells potentially has dual mode of actions (I) targeting immune suppression and thereby potentiating anti-tumor effector T cell responses and (II) direct killing of immunoregulatory antigen-expressing tumor cells.

Circulating T cells that specifically target normal self-proteins expressed by regulatory immune cells were first described in patients with cancer, but can also be detected in healthy individuals. The adaptive immune system is distinguished for its ability to differentiate between self-antigens and foreign antigens. Thus, it was remarkable to discover T cells that apparently lacked tolerance to important self-proteins, eg, IDO, PD-L1, and FoxP3, expressed in regulatory immune cells. The ability of self-reactive T cells to react to and eliminate regulatory immune cells can influence general immune reactions. This suggests that they may be involved in immune homeostasis. It is here proposed that these T cells should be termed antiregulatory T cells (anti-Tregs). The role of anti-Tregs in immune-regulatory networks may be diverse. For example, pro-inflammatory self-reactive T cells that react to regulatory immune cells may enhance local inflammation and inhibit local immune suppression. Further exploration is warranted to investigate their potential role under different malignant conditions and the therapeutic possibilities they possess. Utilizing anti-Tregs for anticancer immunotherapy implies the direct targeting of cancer cells in addition to regulatory immune cells. Anti-Tregs provide the immune system with yet another level of immune regulation and contradict the notion that immune cells involved in the adjustment of immune responses only act as suppressor cells., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

The mechanisms of immune response to cancer have been studied extensively and great effort has been invested into harnessing the therapeutic potential of the immune system. Immunotherapies have seen significant advances in the past 20 years, but the full potential of protective and therapeutic cancer immunotherapies has yet to be fulfilled. The insufficient efficacy of existing treatments can be attributed to a number of biological and technical issues. In this review, we detail the current limitations of immunotherapy target selection and design, and review computational methods to streamline therapy target discovery in a bioinformatics analysis pipeline. We describe specialized bioinformatics tools and databases for three main bottlenecks in immunotherapy target discovery: the cataloging of potentially antigenic proteins, the identification of potential HLA binders, and the selection epitopes and co-targets for single-epitope and multi-epitope strategies. We provide examples of application to the well-known tumor antigen HER2 and suggest bioinformatics methods to ameliorate therapy resistance and ensure efficient and lasting control of tumors.

Monocyte-derived dendritic cells (DCs) used for immunotherapy e.g. against cancer are commonly matured by pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and prostaglandin E(2) although the absence of Toll-like receptor mediated activation prevents secretion of IL-12 from DCs and subsequent efficient induction of type 1 effector T cells. Standard matured clinical grade DCs "sDCs" were compared with DCs matured with either of two type 1 polarizing maturation cocktails; the alpha-type-1 DCs "αDC1s" (TNF-α, IL-1β, IFN-γ, IFN-α, Poly(I:C)) and "mDCs" (monophosphoryl lipid A (MPL), IFN-γ) or a mixed cocktail - "mpDCs", containing MPL, IFN-γ and PGE(2). αDC1s and mDCs secreted IL-12 directly and following re-stimulation with CD40L-expressing cells and they mainly secreted the T effector cell attracting chemokines CXCL10 and CCL5 as opposed to sDCs that mainly secreted CCL22, known to attract regulatory T cells. αDC1s and mDCs were functionally superior to sDCs as they polarized naïve CD4(+) T cells most efficiently into T helper type 1 effector cells and primed more functional MART-1 specific CD8(+) T cells although with variation between donors. αDC1s and mDCs were transiently less capable of CCL21-directed transwell migration than standard matured DCs, likely due to their increased secretion of CCL19, which mediate internalization of CCR7. mpDCs were intermediate between standard and polarized DCs both in terms of IL-12 secretion and transwell migratory ability but functionally they resembled sDCs and strikingly had the highest expression of the inhibitory molecules PD-L1 and CD25. Thus, further studies with type 1 polarized DCs are warranted for use in immunotherapy, but when combined with PGE(2) as in mpDCs, they seems to be less optimal for maturation of DCs., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Although no immunotherapeutic treatment is approved for colorectal cancer (CRC) patients, promising results from clinical trials suggest that several immunotherapeutic strategies may prove efficacious and applicable to this group of patients. This review describes the immunogenicity of CRC and presents the most interesting strategies investigated so far: cancer vaccination including antigen-defined vaccination and dendritic cell vaccination, chemo-immunotherapy, and adoptive cell transfer. Future treatment options as well as the possibility of combining existing therapies will be discussed along with the challenges presented by tumor escape mechanisms.

Survivin is an attractive candidate for cancer immunotherapy since it is overexpressed in most common human cancers, poorly expressed in most normal adult tissues and is essential for cancer cell survival. Previously, we and others have demonstrated that survivin-specific immune responses are present in cancer patients. However, a significant limitation of these findings has been that antigen-specific lysis of tumors was achieved using polyclonal T-cell lines rather than a specific T-cell clone. In the present study we isolated and expanded a survivin specific cytotoxic T lymphocyte (CTL) clone from the peripheral blood of a cancer patient. The survivin specific CTL clone efficiently lysed a large panel of tumor cells of different origin, i.e., breast cancer, colon cancer and melanoma cells. The data support the notion that survivin may serve as a universal target antigen for anti-cancer immunotherapy.

Expression of the cancer-testis antigen Taxol resistance-associated gene-3 (TRAG-3) protein is associated with acquired paclitaxel (Taxol) resistance, and is expressed in various cancer types; e.g., breast cancer, leukemia, and melanoma. Thus, TRAG-3 represents an attractive target for immunotherapy of cancer. To identify HLA-A*02.01-restricted epitopes from TRAG-3, we screened cancer patients for spontaneous cytotoxic T-cell responses against TRAG-3-derived peptides. The TRAG-3 protein sequence was screened for 9mer and 10mer peptides possessing HLA-A*02.01-binding motifs. Of 12 potential binders, 9 peptides were indeed capable of binding to the HLA-A*02.01 molecule, with binding affinities ranging from strong to weak binders. Subsequently, lymphocytes from cancer patients (9 breast cancer patients, 12 melanoma patients, and 13 patients with hematopoietic malignancies) were analyzed for spontaneous reactivity against the panel of peptides by ELISpot assay. Spontaneous immune responses were detected against 8 epitope candidates in 7 of 9 breast cancer patients, 7 of 12 melanoma patients, and 5 of 13 patients with hematopoietic malignancies. In several cases, TRAG-3-specific CTL responses were scattered over several epitopes. Hence, no immunodominance of any single peptide was observed. Furthermore, single-peptide responses were detected in 2 of 12 healthy HLA-A2(+) donors, but no responses were detectable in 9 HLA-A2(-) healthy donors or 4 HLA-A2(-) melanoma patients. The identified HLA-A*02.01-restricted TRAG-3-derived epitopes are targets for spontaneous immune responses in breast cancer, hematopoietic cancer, and melanoma patients. Hence, these epitopes represent potential target structures for future therapeutic vaccinations against cancer, possibly appropriate for strategies that combine vaccination and chemotherapy; i.e., paclitaxel treatment.

Significant advances in the understanding of the cells and molecules involved in tumour/host interactions in humans have been made over the last decades. Thus, through studies of the interactions between cells of the immune system and cancer cells, several tumour antigens and their epitopes recognised by human leucocyte antigen class I-restricted cytotoxic T lymphocytes have been identified. Likewise, specialised antigen presenting cells have been characterised and methods developed that allow the use of such cells in clinical immunology. In the clinic, systemic administration of immune stimulatory cytokines, in particular IL-2, has strengthened the notion that the immune system is capable of mediating rejection of cancer. More recently, more sophisticated methods of inducing anti-cancer immune responses have been pursued, for instance the use of antigen presenting cells in combination with various sources of antigen and cytokines for therapeutic vaccinations against cancer. The present paper summarizes current knowledge in the field of tumour immunology, and reviews various approaches undertaken with the aim of inducing strong anti-tumour responses. To this end, we review data from clinical trials, and discuss the potential of these treatment modalities as an adjunct to conventional modes of cancer treatment. Further, novel methodologies for monitoring and analysing cancer patients over the course of immunotherapeutic treatments are described, and future directions put forward.

Chronic lymphocytic leukemia (CLL) patients with unmutated immunoglobulin heavy chain (IgHV) are at risk of early disease progression compared to patients with mutated IgHV. As a preventive strategy, we treated 19 previously untreated CLL patients with unmutated IgHV in a phase 1/2 trial (clinicaltrials.gov, NCT03939234) exploring the efficacy and toxicity of a therapeutic cancer vaccine containing peptides derived from programmed death ligand 1 (PD-L1) and ligand 2 (PD-L2), hoping to restore immunological control of the disease. According to the International Workshop on Chronic lymphocytic Leukemia (iwCLL) response criteria, no patients obtained a response; however, during follow-up, one patient had complete normalization of the peripheral lymphocyte count and remained in biochemical remission after a follow-up time of 15 months. At the end of treatment, one patient had progressed, and 17 patients had stable disease. During follow-up with a median time of 23.5 months since inclusion, seven patients had progressed, and eight patients had stable disease. The median time to first treatment (TTFT) from diagnosis was 90.3 months with a median follow-up time of 50.1 months. This apparent favorable outcome in TTFT needs to be investigated in a randomized setting, as our population may have been biased. More than 80% of patients obtained vaccine-specific immune responses, confirming the immunogenicity of the vaccine. The vaccine was generally well tolerated with only grade I–II adverse events. Although there were some signs of clinical effects, the vaccine seems to be insufficient as monotherapy in CLL, possibly due to a high tumor burden. The efficacy of the vaccine should preferably be tested in combination with novel targeted therapies or as a consolidating treatment. [ABSTRACT FROM AUTHOR]

CCL22 is a macrophage-derived immunosuppressive chemokine that recruits regulatory T cells through the CCL22:CCR4 axis. CCL22 was shown to play a key role in suppressing anti-cancer immune responses in different cancer types. Recently, we showed that CCL22-specific T cells generated from cancer patients could kill CCL22-expressing tumor cells and directly influence the levels of CCL22 in vitro. The present study aimed to provide a rationale for developing a CCL22-targeting immunotherapy. Vaccination with CCL22-derived peptides induced CCL22-specific T-cell responses in both BALB/c and C57BL/6 mice, assessed by interferon-γ secretion ex vivo. Anti-tumor efficacy of the peptides was evaluated in mouse models engrafted with syngeneic tumor models showing a reduced tumor growth and prolonged survival of the treated mice. Vaccination induced changes in the cellular composition of immune cells that infiltrated the tumor microenvironment assessed with multicolor flow cytometry. In particular, the infiltration of CD8+ cells and M1 macrophages increased, which increased the CD8/Treg and the M1/M2 macrophage ratio. This study provided preclinical evidence that targeting CCL22 with CCL22 peptide vaccines modulated the immune milieu in the tumor microenvironment. This modulation led to an augmentation of anti-tumor responses. This study provided a rationale for developing a novel immunotherapeutic modality in cancer. [ABSTRACT FROM AUTHOR]

Background: Long-term follow-up on a clinical trial of 15 stage III-IV NSCLC patients treated with an Indoleamine 2,3-Dioxygenase (IDO) peptide vaccine (NCT01219348). Methods: Fifteen HLA-A2-positive patients with stable stage III-IV NSCLC after standard chemotherapy were treated with subcutaneous vaccinations (100 μg IDO5 peptide, sequence ALLEIASCL, formulated in 900 μl Montanide) biweekly for 2.5 months and thereafter monthly until progression or up to 5 years. Here we report long-term clinical follow-up, toxicity and immunity. Results: Three of 15 patients are still alive corresponding to a 6-year overall survival of 20 %. Two patients continued monthly vaccinations for 5 years (56 vaccines). One of the two patients developed a partial response (PR) of target lesions in the liver 15 months after the first vaccine and has remained in PR ever since. The other patient had a solitary distant metastasis in a lymph node in retroperitoneum at baseline which normalized during treatment. All following evaluation scans during the treatment have been tumor free. The vaccine was well tolerated for all 5 years with no long-term toxicities registered. The third long-term surviving patient discontinued vaccinations after 11 months due to disease progression. Flow cytometry analyses of PBMCs from the two long-term responders demonstrated stable CD8+ and CD4+ T-cell populations during treatment. In addition, presence of IDO-specific T-cells was detected by IFN-γ Elispot in both patients at several time points during treatment. Conclusion: IDO peptide vaccination was well tolerated for administration up to 5years. Two of 15 patients are long-term responders with ongoing clinical response 6 years after 1st vaccination. [ABSTRACT FROM AUTHOR]

Circulating T cells that specifically target normal self-proteins expressed by regulatory immune cells were first described in patients with cancer, but can also be detected in healthy individuals. The adaptive immune system is distinguished for its ability to differentiate between self-antigens and foreign antigens. Thus, it was remarkable to discover T cells that apparently lacked tolerance to important self-proteins, eg, IDO, PD-L1, and FoxP3, expressed in regulatory immune cells. The ability of self-reactive T cells to react to and eliminate regulatory immune cells can influence general immune reactions. This suggests that they may be involved in immune homeostasis. It is here proposed that these T cells should be termed antiregulatory T cells (anti-Tregs). The role of anti-Tregs in immune-regulatory networks may be diverse. For example, pro-inflammatory self-reactive T cells that react to regulatory immune cells may enhance local inflammation and inhibit local immune suppression. Further exploration is warranted to investigate their potential role under different malignant conditions and the therapeutic possibilities they possess. Utilizing anti-Tregs for anticancer immunotherapy implies the direct targeting of cancer cells in addition to regulatory immune cells. Anti-Tregs provide the immune system with yet another level of immune regulation and contradict the notion that immune cells involved in the adjustment of immune responses only act as suppressor cells. [ABSTRACT FROM AUTHOR]

The era of immunotherapies was unleashed in 2010 with the Food and Drug Administration ( FDA) approval of the first therapeutic vaccine sipuleucel-T as a standard treatment for metastatic prostate cancer. Next, the first immune-activating anticytotoxic lymphocyte antigen-4 ( CTLA-4) antibody ipilimumab exhibiting 'immune checkpoint blockade' was approved by FDA and European Medical Agency ( EMA) for the treatment of patients with metastatic melanoma. New generations of immune checkpoint blockading antibodies targeting programmed cell death 1 ( PD-1) and its ligand ( PD-L1) are now under intense investigation in metastatic melanoma ( MM) and non-small-cell lung cancer ( NSCLC), and impressive clinical results are anticipated. Despite these successes, only a fraction of patients become clinical responders to therapy. Thus, to improve the selection of patients likely to respond, scrutinizing different immune parameters during treatment is essential. In the summary of this PhD thesis, we investigated changes in immune parameters and their possible correlation with clinical efficacy in patients with MM during treatments with the standard chemo- and immunotherapies, temozolomide ( TMZ) and interferon-α2b/interleukin-2 ( IFN-α/ IL-2) immunotherapy. The overall aim was to assess changes in frequency and absolute counts of different immune cell subsets before and after treatment and correlate to clinical benefit. Furthermore, the thesis covers a finalized, clinical phase 1 study in patients with NSCLC testing a peptide vaccination with a HLA-A2-restricted epitope derived from indoleamine 2,3 dioxygenase ( IDO). The overall aim in this trial was to evaluate safety and tolerability of IDO as an anticancer vaccine target in patients with NSCLC and to assess whether immunity correlated to clinical response. [ABSTRACT FROM AUTHOR]

Treg deficiencies are associated with autoimmunity. Conversely, CD4+ and CD8+ Tregs accumulate in the tumor microenvironment and are associated with prevention of antitumor immunity and anticancer immunotherapy. Recently, CD4+ Tregs have been much studied, but little is known about CD8+ Tregs and the antigens they recognize. Here, we describe what we believe to be the first natural target for CD8+ Tregs. Naturally occurring HLA-A2-restricted CD8+ T cells specific for the antiinflammatory molecule heme oxygenase-1 (HO-1) were able to suppress cellular immune responses with outstanding efficacy. HO-1-specific CD8+ T cells were detected ex vivo and in situ among T cells from cancer patients. HO-1-specific T cells isolated from the peripheral blood of cancer patients inhibited cytokine release, proliferation, and cytotoxicity of other immune cells. Notably, the inhibitory effect of HO-1-specific T cells was far more pronounced than that of conventional CD4+CD25+CD127- Tregs. The inhibitory activity of HO-1-specific T cells seemed at least partly to be mediated by soluble factors. Our data link the cellular stress response to the regulation of adaptive immunity, expand the role of HO-1 in T cell-mediated immunoregulation, and establish a role for peptide-specific CD8+ T cells in regulating cellular immune responses. Identification of potent antigen-specific CD8+ Tregs may open new avenues for therapeutic interventions in both autoimmune diseases and cancer. [ABSTRACT FROM AUTHOR]

Based on the detection of spontaneous immune responses in cancer patients with cancer of different origin, Bcl-X(L) was recently described as a highly interesting tumor antigen recognized by CD8 positive cytotoxic T lymphocytes. To further characterize Bcl-X(L) as a tumor antigen we isolated and expanded Bcl-X(L) specific T cells from the peripheral blood of a breast cancer patient hosting a strong Bcl-X(L) specific T cell response. We describe that HLA-A2 restricted Bcl-X(L) specific T cell clones very efficiently lyse peptide pulsed T2 cells. Furthermore, tumor cell lines of different origin, i.e., breast cancer, colon cancer, and melanoma, are efficiently lysed in an HLA-dependent manner. Finally, ex vivo-isolated leukemia cells, but not non-malignant B and T cells are killed by Bcl-X(L) specific T cells. Our data underline Bcl-X(L) as an universal tumor antigen widely applicable in specific anticancer immunotherapy. [ABSTRACT FROM AUTHOR]

Recently, it was described that an HLA-A24 restricted peptide derived from the survivin splice variant survivin-2B can be recognized by CD8(+) cytotoxic T-cells. The identification of an HLAA24 epitope is critical for survivin-based immunotherapy as HLA-24 is the most frequent HLA allele in Asia. Consequently, this survivin-2B epitope is already a target in a clinical study in patients with advanced or recurrent colorectal cancer expressing survivin. However, the splice variant survivin-2B has been described to be pro-apoptotic, and is only expressed at low levels in most malignant tissues. Furthermore, survivin-2B expression are significantly decreased in later tumor stages and inversely correlated with tumor differentiation and invasion. Consequently, survivin is a more general vaccination candidate than the splice variant survivin-2B. Here, we on the basis of spontaneous immune responses in HLA-A24+ cancer patients describes that a HLA-A24-restricted survivin epitopes does indeed exist. Consequently, this epitope is an attractive target for the ongoing survivin-based peptide immunotherapy against cancer. [ABSTRACT FROM AUTHOR]

Background: Differences in HLA allele frequencies between the diseased and healthy populations may signify efficient immune responses, a notion that has been successfully tested for infectious diseases or for association with genetic elements involved in a distinct type of immunity. This retrospective study is intended to detect differences in MHC class I carrier frequencies of advanced melanoma patients compared to healthy bone marrow donors. Methods: The HLA-A and -B carrier frequencies of 748 stage IV melanoma patients retrieved from serotyping at 6 different centers in Germany were compared using a chi-square test to 13,386 fully HLA typed bone marrow donors registered in the German national bone marrow donor registry. Results: The comparison of HLA carrier frequencies in advanced cancer patients with healthy bone marrow donors revealed a significant decrease in HLA-B8 carrier frequencies, which was also apparent in patients with advanced disease compared to patients with loco-regional disease. Conclusion: The data suggest that protective immune responses restricted to distinct MHC class I molecules may be operational in a subset of melanoma patients, which is the prerequisite for a large scale screen for the corresponding epitopes. Alternatively, the known association of the ancestral haplotype HLA-A1, -B8 and -DR3 with genetic elements such as distinct TNF-α alleles might have a protective effect on disease progression. In any case, identification of the cause of protection within this patient subset might lead to a significant improvement in the efficacy of current immunotherapeutic approaches. [ABSTRACT FROM AUTHOR]

Interleukin 2 (IL-2) is a promising immunotherapeutic agent for the treatment of metastatic melanoma and renal cell carcinoma. Systemic administration of high dose IL-2 produces objective responses in up to 25% of melanoma patients, and a low but significant proportion of these patients experience durable responses. Nevertheless, the cells and molecules responsible for induction of tumor regression over the course of IL-2 treatment remain unknown. New strategies in tumor immunotherapy have evolved over the past decade as a consequence of significant progress in the field, in particular with respect to the characterization of peptide epitopes derived from tumor associated antigens, and the role of antigen presenting cells in the initiation of cellular immune responses. Alongside with these factual as well as conceptual advances, new methods have been developed to monitor and characterize anti-tumor T cell responses in cancer patients. Application of these tools to dissect anti-tumor responses has demonstrated that various immune therapeutic approaches can induce powerful systemic anti-tumor cytotoxic T lymphocyte (CTL) responses. However, only limited efforts have been made to use present days tool to analyze anti-tumor immune responses in patients treated with IL-2 based immunotherapy. We have examined CTL responses against known tumor antigens in melanoma patients over the course of IL-2 based immunotherapy (electrochemotherapy). Surprisingly, anti-tumor CTL responses significantly declined upon initiation of therapy, but reappeared when IL-2 administration was paused. Molecular analyses of the clonotypic composition of responding T cells demonstrated that new clones emerged over the course of treatment, and that tumor-specific T cells that had left the peripheral blood could subsequently be detected at the tumor site. These data provide new insight into the biological actions of IL-2 and highlight the difficulties associated with the monitoring of anti-tumor immune responses. This underlines the importance of frequent sampling of blood and tumor biopsies to be analyzed with a combination of state of the art technologies in order to gain detailed information on the interactions between cancer cells and cells of the immune system. [Copyright &y& Elsevier]

Simple Summary: Basal cell carcinoma is the most common skin cancer and new treatments for patients with widespread and numerous tumors are lacking. In a previous study treating patients with multiple myeloma with a peptide vaccine called IO103 against an immune checkpoint molecule called programmed death ligand 1, two cases of basal cell carcinoma regressed. The aim of the present study was to assess the effect of vaccination with IO103 in ten patients with basal cell carcinoma. Patients were vaccinated with Montanide as adjuvant up to nine times during six months. Regression in tumor size of at least 30% was seen in five of 18 tumors, two of which showed complete regression. Vaccinations resulted in immune responses against the vaccine in blood samples from nine of ten patients and in skin samples from five of nine patients. The findings suggest that the vaccine may be effective against some basal cell carcinomas. Antitumor activity of immune checkpoint blocking antibodies against programmed death 1 (PD-1) in basal cell carcinoma (BCC) has been described. IO103 is a peptide vaccine against the major PD-1 ligand PD-L1. A phase IIa study of vaccination with IO103 and Montanide adjuvant was conducted in patients with resectable BCC (NCT03714529). Vaccinations were given six times every 2 weeks (q2w), followed by three vaccines q4w in responders. Primary endpoints were clinical responses of target tumors, change in target tumor size and immune responses to the vaccine. Secondary endpoint was safety. One tumor per patient was designated target tumor and biopsied twice during the course of vaccination. Synchronous non-target BCCs were not biopsied during vaccinations. Ten patients were vaccinated (six patients received six vaccinations and four patients received nine vaccinations). A partial response (PR) was seen in two target tumors. Two complete responses (CR) and one PR were observed in eight non-target tumors in four patients. No tumors progressed. Related adverse events were grade 1 and reversible. Immune responses against IO103 were induced in blood samples from nine of ten and skin-infiltrating lymphocytes from five of the nine patients. The regressions seen in non-target tumors suggest that IO103 may be effective against a subtype of BCC. [ABSTRACT FROM AUTHOR]

Philadelphia chromosome-negative chronic myeloproliferative neoplasms (MPN) are neoplastic diseases of the hematopoietic stem cells in the bone marrow. MPN are characterized by chronic inflammation and immune dysregulation. Of interest, the potent immunostimulatory cytokine interferon-α has been used to treat MPN for decades. A deeper understanding of the anti-cancer immune response and of the different immune regulatory mechanisms in patients with MPN has paved the way for an increased perception of the potential of cancer immunotherapy in MPN. Therapeutic vaccination targeting the driver mutations in MPN is one recently described potential new treatment modality. Furthermore, T cells can directly react against regulatory immune cells because they recognize proteins like arginase and programmed death ligand 1 (PD-L1). Therapeutic vaccination with arginase or PD-L1 therefore offers a novel way to directly affect immune inhibitory pathways, potentially altering tolerance to tumor antigens like mutant CALR and mutant JAK2. Other therapeutic options that could be used in concert with therapeutic cancer vaccines are immune checkpoint–blocking antibodies and interferon-α. For more advanced MPN, adoptive cellular therapy is a potential option that needs more preclinical investigation. In this review, we summarize current knowledge about the immune system in MPN and discuss the many opportunities for anti-cancer immunotherapy in patients with MPN. [ABSTRACT FROM AUTHOR]

We recently described naturally occurring PD-L1-specific T cells that recognize PD-L1-expressing immune cells as well as malignant cells. In the present study, we investigated whether the immunogenicity of a dendritic cell (DC)-based vaccine could be influenced by co-stimulation with a known PD-L1-derived epitope. We incubated a PD-L1-derived peptide epitope (19 amino acids long) or a control peptide (an irrelevant HIV epitope) with peripheral blood mononuclear cells from patients with malignant melanoma who had received a DC-based vaccine. We observed a significantly higher number of T cells that reacted to the vaccine in cultures that had been co-stimulated with the PD-L1 peptide epitope compared to cultures incubated with control peptide. Next, we characterized a novel PD-L1-derived epitope (23 amino acids long) and found that co-stimulation with both PD-L1 epitopes boosted the immune response elicited by the DC vaccine even further. Consequently, we observed a significant increase in the number of vaccine-reacting T cellsin vitro. In conclusion, activation of PD-L1-specific T cells may directly modulate immunogenicity of DC vaccines. Addition of PD-L1 epitopes may thus be an easily applicable and attractive option to augment the effectiveness of cancer vaccines and other immunotherapeutic agents. [ABSTRACT FROM PUBLISHER]