Dendritic cell-based immunotherapy in non-small cell lung cancer: a comprehensive critical review.

Despite treatment advances through immunotherapies, including anti-PD-1/PD-L1 therapies, the overall prognosis of non-small cell lung cancer (NSCLC) patients remains poor, underscoring the need for novel approaches that offer long-term clinical benefit. This review examined the literature on the subject over the past 20 years to provide an update on the evolving landscape of dendritic cell-based immunotherapy to treat NSCLC, highlighting the crucial role of dendritic cells (DCs) in immune response initiation and regulation. These cells encompass heterogeneous subsets like cDC1s, cDC2s, and pDCs, capable of shaping antigen presentation and influencing T cell activation through the balance between the Th1, Th2, and Th17 profiles and the activation of regulatory T lymphocytes (Treg). The intricate interaction between DC subsets and the high density of intratumoral mature DCs shapes tumor-specific immune responses and impacts therapeutic outcomes. DC-based immunotherapy shows promise in overcoming immune resistance in NSCLC treatment. This article review provides an update on key clinical trial results, forming the basis for future studies to characterize the role of different types of DCs in situ and in combination with different therapies, including DC vaccines.

Trichostatin A-modified vaccine provides superior protection against ovarian cancer formation and development.

More attention has been paid to immunotherapy for ovarian cancer and the development of tumor vaccines. We developed a trichostatin A (TSA)-modified tumor vaccine with potent immunomodulating activities that can inhibit the growth of ovarian cancer in rats and stimulate immune cell response in vivo. TSA-treated Nutu-19 cells inactivated by X-ray radiation were used as a tumor vaccine in rat ovarian cancer models. Prophylactic and therapeutic experiments were performed with TSA-modified tumor vaccine in rats. Flow cytometry and ELISpot assays were conducted to assess immune response. Immune cell expression in the spleen and thymus were detected by immunohistochemical staining. GM-CSF, IL-7, IL-17, LIF, LIX, KC, MCP-1, MIP-2, M-CSF, IP-10/CXCL10, MIG/CXCL9, RANTES, IL-4, IFN-γ, and VEGF expressions were detected with Milliplex Map Magnetic Bead Panel immunoassay. TSA vaccination in therapeutic and prophylactic models could effectively stimulate innate immunity and boost the adaptive humoral and cell-mediated immune responses to inhibit the growth and tumorigenesis of ovarian cancer. This vaccine stimulated the thymus into reactivating status and enhanced infiltrating lymphocytes in tumor-bearing rats. The expression of key immunoregulatory factors were upregulated in the vaccine group. The intensities of infiltrating CD4+ and CD8+ T cells and NK cells were significantly increased in the vaccine group compared to the control group (P<0.05). This protection was mainly dependent on the IFN-γ pathway and, to a much lesser extent, by the IL-4 pathway. The tumor cells only irradiated by X-ray as the control group still showed a slight immune effect, indicating that irradiated cells may also cause certain immune antigen exposure, but the efficacy was not as significant as that of the TSA-modified tumor vaccine. Our study revealed the potential application of the TSA-modified tumor vaccine as a novel tumor vaccine against tumor refractoriness and growth. These findings offer a better understanding of the immunomodulatory effects of the vaccine against latent tumorigenesis and progression. This tumor vaccine therapy may increase antigen exposure, synergistically activate the immune system, and ultimately improve remission rates. A vaccine strategy designed to induce effective tumor immune response is being considered for cancer immunotherapy.

Vaccimel immunization is associated with enhanced response to treatment with anti-PD-1 monoclonal antibodies in cutaneous melanoma patients - a case reports study.

Cancer vaccines are gaining ground as immunotherapy options. We have previously demonstrated in cutaneous melanoma (CM) patients that adjuvant treatment with VACCIMEL, a mixture of four irradiated CM cell lines co-adjuvanted with BCG and GM-CSF, increases the cellular immune response to melanocyte differentiation antigens, cancer-testis antigens and neoantigens, with respect to basal levels. On the other hand, it is also known that treatment with anti-PD-1 monoclonal antibodies (MAbs), acting on pre-existing tumor-reactive lymphocytes, induces clinical responses in CM patients, albeit in a fraction of treated patients. A combination of both treatments would appear therefore desirable. In this paper, we describe CM patients who, having progressed even years after vaccination, were treated with anti-PD-1 MAbs. In 5/5 of such progressor patients, complete responses were obtained which lasted between 3 and 65+ months. Three of the patients remain disease-free and two recurred. One of the patients passed away after a recurrence of brain metastases. We suggest that clonally expanded reactive lymphocytes induced by VACCIMEL partially remain as memory cells, which may be recalled after tumor recurrence and may foster ulterior activity of anti-PD-1 MAbs.

Long-term antigen-specific immune response by an oncolytic adenovirus encoding SP-SA-E7-4-1BBL in HPV-16 cancer model.

BACKGROUND: To describe an oncolytic adenovirus (OAd) encoding SP-SA-E7-4-1BBL that is capable of inducing tumor regression in therapeutic assays. Herein, we tested whether the antitumor effect is given by the induction of a tumor-specific immune response, as well as the minimum dose needed to elicit antitumor protection and monitor the OAd biodistribution over time. METHODS AND RESULTS: C57BL/6 mice (n = 5) per group were immunized twice with OAds encoding SP-SA-E7-4-1BBL, SA-E7-4-1BBL, or SP-SA-4-1BBL and challenged with TC-1 cancer cells. The DNA construct SP-SA-E7-4-1BBL was employed as a control via biolistic or PBS injection. Groups without tumor development at 47 days were rechallenged with TC-1 cells, and follow-up lasted until day 90. The minimum dose of OAd to induce the antitumor effect was established by immunization using serial dilution doses. The cytometry bead assay and the ELISpot assay were used to evaluate cytokine release in response to ex vivo antigenic stimulation. The distribution profile of the OAd vaccine was evaluated in the different organs by histological, immunohistochemical and qPCR analyses. The OAd SP-SA-E7-4-1BBL-immunized mice did not develop tumors even in a rechallenge. A protective antitumor effect was observed from a dose that is one hundredth of most reports of adenoviral vaccines. Immunization with OAd increases Interferon-gamma-producing cells in response to antigen stimulation. OAd was detected in tumors over time, with significant morphological changes, contrary to nontumor tissues. CONCLUSIONS: The OAd SP-SA-E7-4-1BBL vaccine confers a prophylactic, safe, long-lasting, and antigen-dependent antitumor effect mediated by a Th1 antitumor immune response.

Current approaches in glioblastoma multiforme immunotherapy.

Glioblastoma multiform (GBM) is the most prevalent CNS (central nervous system) tumor in adults, with an average survival length shorter than 2 years and rare metastasis to organs other than CNS. Despite extensive attempts at surgical resecting, the inherently permeable nature of this disease has rendered relapse nearly unavoidable. Thus, immunotherapy is a feasible alternative, as stimulated immune cells can enter into the remote and inaccessible tumor cells. Immunotherapy has revolutionized patient upshots in various malignancies and might introduce different effective ways for GBM patients. Currently, researchers are exploring various immunotherapeutic strategies in patients with GBM to target both the innate and acquired immune responses. These approaches include reprogrammed tumor-associated macrophages, the use of specific antibodies to inhibit tumor progression and metastasis, modifying tumor-associated macrophages with antibodies, vaccines that utilize tumor-specific dendritic cells to activate anti-tumor T cells, immune checkpoint inhibitors, and enhanced T cells that function against tumor cells. Despite these findings, there is still room for improving the response faults of the many currently tested immunotherapies. This study aims to review the currently used immunotherapy approaches with their molecular mechanisms and clinical application in GBM.

ICAM2 is related to good prognosis in dendritic cell immunotherapy for cancer.

Objective: To evaluate the behavior of adhesion molecules ICAM-1 and ICAM-2 in dendritic cell (DC) immunotherapy. Materials & methods: 88 female Balb/c mice were divided into experimental groups. Tumors and lymph nodes were evaluated 7 and 14 days after immunotherapy. Results: Higher mean fluorescence intensity of ICAM-1 in the lymph nodes and tumors in the tumor group at 14 days was observed. Higher mean fluorescence intensity of ICAM-2 in the tumor DC vaccine group was observed after 14 days. A positive correlation was observed in the lymph nodes with ICAM-1 against tumoral volume in the tumor group. A negative correlation was found between ICAM-2 and tumoral volume in the lymph nodes of the tumor group. Conclusion: An increase in ICAM-2 in tumor DC vaccine and a decrease in ICAM-1 suggests the DC vaccine positively influences the immune system and that ICAM-2 could be a marker of good prognosis.

Dendritic cell vaccines are a type of immunotherapy that can reduce tumor volume and increase the expression of immune proteins that fight cancer. However, some improvements are needed to better analyze tumor development and cell characteristics in patients given these vaccines. This research was designed to clearly describe what happens to the body's natural defense during treatment with dendritic cell vaccines. Animals were induced to develop breast cancer and parts of their immune system were analyzed after receiving a dendritic cell vaccine. A specific molecule, called ICAM-2, which is involved in the immune response, was linked to a reduction in tumor volume. The authors conclude that ICAM-2 might be a marker of good prognosis in patients receiving a dendritic cell vaccine.

Prophylactic cancer vaccines: development and challenges for HBV and HPV vaccines in Latin America.

Vaccines against hepatitis B virus (HBV) and human papillomaviruses (HPV) are two safe and highly effective vaccines that were developed at the end of the 20th century and can prevent human cancer. HBV vaccine prevents liver cancer, and HPV prevents cervical and other HPV-related cancers. Starting with the immunogen identification, 15 years were necessary to reach the industrial production of HBV vaccine, and 20 years, for the HPV vaccines. However, while HBV vaccines have been commercially available for over 40 years and are used in most countries, there are still significant challenges to achieve universal childhood immunization against hepatitis B. Similarly, HPV vaccines have been commercially available for 17 years, and yet, countries with higher cervical cancer still have the lowest HPV vaccination rates. We describe the development of HBV and HPV vaccines and discuss the challenges to reaching equitable access to these vaccines in Latin America.

The role of immune subtyping in glioma mRNA vaccine development.

Studies on the development of mRNA vaccines for central nervous system tumors have used gene expression profiles, clinical data and RNA sequencing from sources such as The Cancer Genome Atlas and Chinese Glioma Genome Atlas to identify effective antigens. These studies revealed several immune subtypes of glioma, each one linked to unique prognoses and genetic/immune-modulatory changes. Potential antigens include ARPC1B, BRCA2, COL6A1, ITGB3, IDH1, LILRB2, TP53 and KDR, among others. Patients with immune-active and immune-suppressive phenotypes were found to respond better to mRNA vaccines. While these findings indicate the potential of mRNA vaccines in cancer therapy, further research is required to optimize administration and adjuvant selection, and precisely identify target antigens.

Scientists study special vaccines for hard-to-treat brain tumors. They looked at things, such as information about patients and the small parts of cells that make up the tumor, to find ways to help. They found that brain tumors can make our body's defenses act differently. They also found some possible targets and unique defense patterns that are special to each patient when fighting these tumors. Patients with these special defenses and good targets might respond better to treatment with vaccines. This is exciting because it means that in the future, we might have treatments made for each person. But we still need to do more research to figure out how to get these vaccines to the tumor, so this research gives us hope that we can find better treatments and more choices for people with brain cancer. If we keep researching, we might find even better treatments in the future.

Whole tumour cell-based vaccines: tuning the instruments to orchestrate an optimal antitumour immune response.

Immunotherapy, particularly those based on immune checkpoint inhibitors (ICIs), has become a useful approach for many neoplastic diseases. Despite the improvements of ICIs in supporting tumour regression and prolonging survival, many patients do not respond or develop resistance to treatment. Thus, therapies that enhance antitumour immunity, such as anticancer vaccines, constitute a feasible and promising therapeutic strategy. Whole tumour cell (WTC) vaccines have been extensively tested in clinical studies as intact or genetically modified cells or tumour lysates, injected directly or loaded on DCs with distinct adjuvants. The essential requirements of WTC vaccines include the optimal delivery of a broad battery of tumour-associated antigens, the presence of tumour cell-derived molecular danger signals, and adequate adjuvants. These factors trigger an early and robust local innate inflammatory response that orchestrates an antigen-specific and proinflammatory adaptive antitumour response capable of controlling tumour growth by several mechanisms. In this review, the strengths and weaknesses of our own and others' experiences in studying WTC vaccines are revised to discuss the essential elements required to increase anticancer vaccine effectiveness.

Advances in cancer immunotherapies.

Therapeutic modalities that engage the immune system to recognize and eliminate cancer, known as cancer immunotherapy, has emerged as a distinct pillar of cancer therapy. Among the most promising treatment approaches are therapeutic vaccines, immune checkpoint blockade, bispecific T-cell engagers (BiTEs) and adoptive cell therapies. These approaches share a common mechanism of action, which is elicitation of a T-cell-based immune response, either endogenous or engineered, against tumor antigens, but interactions between the innate immune system, particularly antigen-presenting cells, and immune effectors also underlie the efficacy of cancer immunotherapies and approaches engaging these cells are also under development. To view this SnapShot, open or download the PDF.

Single immunizations of self-amplifying or non-replicating mRNA-LNP vaccines control HPV-associated tumors in mice.

As mRNA vaccines have proved to be very successful in battling the coronavirus disease 2019 (COVID-19) pandemic, this new modality has attracted widespread interest for the development of potent vaccines against other infectious diseases and cancer. Cervical cancer caused by persistent human papillomavirus (HPV) infection is a major cause of cancer-related deaths in women, and the development of safe and effective therapeutic strategies is urgently needed. In the present study, we compared the performance of three different mRNA vaccine modalities to target tumors associated with HPV-16 infection in mice. We generated lipid nanoparticle (LNP)-encapsulated self-amplifying mRNA as well as unmodified and nucleoside-modified non-replicating mRNA vaccines encoding a chimeric protein derived from the fusion of the HPV-16 E7 oncoprotein and the herpes simplex virus type 1 glycoprotein D (gDE7). We demonstrated that single low-dose immunizations with any of the three gDE7 mRNA vaccines induced activation of E7-specific CD8+ T cells, generated memory T cell responses capable of preventing tumor relapses, and eradicated subcutaneous tumors at different growth stages. In addition, the gDE7 mRNA-LNP vaccines induced potent tumor protection in two different orthotopic mouse tumor models after administration of a single vaccine dose. Last, comparative studies demonstrated that all three gDE7 mRNA-LNP vaccines proved to be superior to gDE7 DNA and gDE7 recombinant protein vaccines. Collectively, we demonstrated the immunogenicity and therapeutic efficacy of three different mRNA vaccines in extensive comparative experiments. Our data support further evaluation of these mRNA vaccines in clinical trials.

A Brief Overview of Cancer Vaccines.

ABSTRACT: Vaccine strategies for cancer differ from infectious disease in focusing mainly on clearing rather than preventing disease. Here we survey general vaccine strategies and combination therapy concepts being investigated for cancer treatment, with a focus on tumor antigens rather than cancer-inducing viruses or microorganisms. Many tumor antigens are "altered-self" and tend to arouse weaker immune responses than "foreign" antigens expressed by infectious agents. Further, unlike an infectious disease patient, a cancer patient's immune system is damaged, suppressed, or senescent and mainly tolerant of their disease. Thus, vaccine efficacy in a cancer patient will rely upon adjuvant or combination treatments that correct the inflammatory tumor microenvironment and degrade tumoral immunosuppression that dominates patient immunity. This brief overview is aimed at new researchers in cancer immunology seeking an overview of vaccine concepts to eradicate malignancy by provoking a selective immune attack.

Adjuvant properties of IFN-γ and GM-CSF in the scFv6.C4 DNA vaccine against CEA-expressing tumors.

Tumor-associated carcinoembryonic antigen (CEA) is a natural target for vaccines against colorectal cancers. Our previous experience with a DNA vaccine with scFv6.C4, a CEA surrogate, showed a CEA-specific immune response with 40% of tumor-free mice after challenge with B16F10-CEA and 47% with MC38-CEA cells. These percentages increased to 63% after using FrC as an adjuvant. To further enhance the vaccine efficacy, we tested GM-CSF and IFNγ as adjuvants. C57BL/6J-CEA2682 mice were immunized 4 times with uP-PS/scFv6.C4, uP-PS/scFv6.C4 + uP-IFNγ, or uP-PS/scFv6.C4 + uP-GMCSF. After one week, the mice were challenged with MC38-CEA, and tumor growth was monitored over 100 days. Immunization with scFv6.C4 and scFv6.C4 + GM-CSF resulted in a gradual increase in the anti-CEA antibody titer, while scFv6.C4 + IFNγ immunization led to a rapid and sustained increase in the titer. The addition of IFNγ also induced higher CD4 + and CD8 + responses. When challenged, almost 80% of the scFv6.C4 + IFNγ-vaccinated mice did not develop tumors, while the others had a significant tumor growth delay. The probability of being tumor-free was 2700% higher using scFv6.C4 + IFNγ than scFv6.C4. The addition of GM-CSF had no additional effect on tumor protection. DNA immunization with scFv6.C4 + IFNγ, but not GM-CSF, increased the antitumor effect via readily sustained specific humoral and cytotoxic responses to CEA.

Mechanism of action of DSP-7888 (adegramotide/nelatimotide) Emulsion, a peptide-based therapeutic cancer vaccine with the potential to turn up the heat on non-immunoreactive tumors.

BACKGROUND: Wilms' tumor 1 (WT1) is highly expressed in various solid tumors and hematologic malignancies. DSP-7888 (adegramotide/nelatimotide) Emulsion is an investigational therapeutic cancer vaccine comprising three synthetic epitopes derived from WT1. We evaluated the mechanism of action of DSP-7888 Emulsion, which is hypothesized to induce WT1-specific cytotoxic T lymphocytes (CTLs) and helper T lymphocytes (HTLs). METHODS: The ability of nelatimotide and adegramotide to induce WT1-specific CD8+ T cells and CD4+ T cells was assessed in human peripheral blood mononuclear cells (PBMCs). The ability of DSP-7888 Emulsion to induce WT1-specific CTLs in vivo was assessed using human leukocyte antigen-I (HLA-I) transgenic mice. To assess how adegramotide, the helper peptide in DSP-7888 Emulsion, enhances WT1-specific CTLs, HLA-I transgenic mice were administered DSP-7888 or nelatimotide-only Emulsion. Interferon-gamma secretion under antigen stimulation by splenocytes co-cultured with or without tumor cells was then quantified. The effects of combination treatment with DSP-7888 Emulsion and an anti-programmed cell death protein 1 (PD-1) antibody on tumor volume and the frequency of tumor-infiltrating WT1-specific T cells were assessed in HLA-I transgenic mice implanted with WT1 antigen-positive tumors. RESULTS: The peptides in DSP-7888 Emulsion were shown to induce WT1-specific CTLs and HTLs in both human PBMCs and HLA-I transgenic mice. Unlike splenocytes from nelatimotide-only Emulsion-treated mice, splenocytes from DSP-7888 Emulsion-treated mice exhibited high levels of interferon-gamma secretion, including when co-cultured with tumor cells; interferon-gamma secretion was further enhanced by concomitant treatment with anti-PD-1. HLA-I transgenic mice administered DSP-7888 Emulsion plus anti-PD-1 experienced significantly greater reductions in tumor size than mice treated with either agent alone. This reduction in tumor volume was accompanied by increased numbers of tumor-infiltrating WT1-specific CTLs. CONCLUSIONS: DSP-7888 Emulsion can promote both cytotoxic and helper T-cell-mediated immune responses against WT1-positive tumors. Adegramotide enhances CTL numbers, and the CTLs induced by treatment with both nelatimotide and adegramotide are capable of functioning within the immunosuppressive tumor microenvironment. The ability of anti-PD-1 to enhance the antitumor activity of DSP-7888 Emulsion in mice implanted with WT1-positive tumors suggests the potential for synergy.

Triiodothyronine-stimulated dendritic cell vaccination boosts antitumor immunity against murine colon cancer.

Given the ability of dendritic cells (DCs) to modulate other immune players, their manipulation holds great potential for inducing efficient antitumor immunity. However, DC vaccine manufacturing deserve optimization since tumor cell cargo and DC functional state induced by maturation signals influence their in vivo immunogenic potential. We reported that triiodothyronine (T3) stimulates mice DCs' maturation and their ability to promote pro-inflammatory and cytotoxic T-cell responses. This study aimed to evaluate the efficacy of T3-conditioned DC vaccination in a murine model of colon carcinoma, deciphering the molecular players involved; and to examine the effects of T3 on the maturation and activation of human DCs (huDCs). Bone marrow-derived DCs were exposed to T3 and MC38 cancer cells that underwent cell death (MC38-Apo/Nec) by UVB irradiation. Our results showed that MC38-Apo/Nec cells are efficiently uptaken by DCs and that T3 upregulates CD86 expression with increased production of the pro-inflammatory cytokines IL-12, IL-6 and TGF-ß. In a colon cancer model, vaccination with T3-stimulated and tumor antigen-loaded DCs inhibited tumor growth in wild type mice, an effect that was eliminated in IL-17-deficient animals. Notably, secretion of high levels of IFN-γ and IL-17, induction of Th1, Th17 and tumor-specific cytotoxic T lymphocytes characterized the antitumor response upon vaccination. Moreover, our initial findings demonstrated a significant increase in CD86 expression and IL-12 production by huDCs induced by T3. Overall, these results reinforce the adjuvant properties of T3-conditioned DCs to potentiate T-cell-mediated antitumor immunity and support promising advances in the translation process to human oncotherapy.

Domain-level epitope mapping of polyclonal antibodies against HER-1 and HER-2 receptors using phage display technology.

HER-1 and HER-2 are tumor-associated antigens overexpressed in several epithelial tumors, and successfully targeted by therapeutic approaches against cancer. Vaccination with their recombinant extracellular domains has had encouraging results in the pre-clinical setting. As complex humoral responses targeting multiple epitopes within each antigen are the ultimate goal of such active immunotherapy strategies, molecular dissection of the mixture of antibody specificities is required. The current work exploits phage display of antigenic versions of HER-1 and HER-2 domains to accomplish domain-level epitope mapping. Recognition of domains I, III and IV of both antigens by antibodies of immunized mice was shown, indicating diverse responses covering a broad range of antigenic regions. The combination of phage display and site-directed mutagenesis allowed mutational screening of antigen surface, showing polyclonal antibodies' recognition of mutated receptor escape variants known to arise in patients under the selective pressure of the anti-HER-1 antibody cetuximab. Phage-displayed HER domains have thus the potential to contribute to fine specificity characterization of humoral responses during future development of anti-cancer vaccines.

Near-Complete Remission of Glioblastoma in a Patient Treated with an Allogenic Dendritic Cell-Based Vaccine: The Role of Tumor-Specific CD4+T-Cell Cytokine Secretion Pattern in Predicting Response and Recurrence.

Immunotherapy has brought hope to the fight against glioblastoma, but its efficacy remains unclear. We present the case of CST, a 25-year-old female patient with a large right-hemisphere glioblastoma treated with a dendritic-tumor cell fusion vaccine. CST showed a near-complete tumor response, with a marked improvement in her functional status and simultaneous increases in tumor-specific CD8+ and CD4+ T cells. Two months before recurrence, the frequency of tumor-specific T cells decreased, while that of IL-17 and CD4+ T cells increased. CST passed away 15 months after enrollment. In this illustrative case, the tumor-specific CD4+ T-cell numbers and phenotype behaved as treatment efficacy biomarkers, highlighting the key role of the latter in glioblastoma immunotherapy.

An Update of Cutaneous Melanoma Patients Treated in Adjuvancy With the Allogeneic Melanoma Vaccine VACCIMEL and Presentation of a Selected Case Report With In-Transit Metastases.

The CSF-470 vaccine (VACCIMEL) plus BCG and GM-CSF as adjuvants has been assayed in cutaneous melanoma patients. In the adjuvant randomized Phase II study CASVAC-0401, vaccinated patients had longer distant metastasis-free survival (DMFS) than those treated with IFNα2b. Five years after locking the data, an actualization was performed. The benefit in DMFS was maintained in the vaccinated group versus the IFNα2b-treated group (p = 0.035), with a median DMFS of 96 months for VACCIMEL and 13 months for IFNα2b. The favorable risk-benefit ratio was maintained. DMFS was also analyzed as a single cohort in all the IIB, IIC, and III patients (n = 30) who had been treated with VACCIMEL. The median DMFS was 169 months, and at 48 months follow-up, it was 71.4%, which was not statistically different from DMFS of previously published results obtained in adjuvancy with ipilimumab, pembrolizumab, nivolumab, or dabrafenib/trametinib. The possible toxicity of combining VACCIMEL with anti-immune checkpoint inhibitors (ICKi) was analyzed, especially since VACCIMEL was co-adjuvated with BCG in every vaccination. A patient with in-transit metastases was studied to produce a proof of concept. During treatment with VACCIMEL, the patient developed T-cell clones reactive towards tumor-associated antigens. Three years after ending the VACCIMEL study, the patient progressed and was treated with ICKi. During ICKi treatment, the patient did not reveal any toxicity due to previous BCG treatment. When she recurred after a 4-year treatment with nivolumab, a biopsy was obtained and immunohistochemistry and RNA-seq were performed. The tumor maintained expression of tumor-associated antigens and HLA-I and immune infiltration, with immunoreactive and immunosuppressive features. VACCIMEL plus BCG and GM-CSF is an effective treatment in adjuvancy for stages IIB, IIC, and III cutaneous melanoma patients, and it is compatible with subsequent treatments with ICKi.

Potential mechanisms involved on how systemic IgG antibodies specific to vascular endothelial growth factor (VEGF) and induced by active immunotherapy decrease platelet derived free-VEGF.

CIGB-247 is a vascular endothelial growth factor (VEGF)-based active immunotherapy and it is currently under investigation for cancer treatment. This specific active immunotherapy encompasses two vaccine candidates that use a human VEGF variant molecule as antigen, in combination with two clinically tested adjuvants: VSSP or aluminum phosphate. CIGB-247 has been evaluated in patients with advanced solid tumors, recruited in two phase I clinical trials, and it has been shown to be safe and immunogenic by activating both cellular and humoral immune responses against human VEGF. The immunization induces specific IgG antibodies, and also shows as effect, the reduction of free-VEGF levels within platelets (platelet-derived free VEGF). The production of systemic IgG antibodies and the presence of VEGF in another compartment, almost exclusively within platelets, have arisen some questions about this effect detected in the vaccinated-cancer patients. Based on some relevant published works about platelet endocytosis and VEGF pharmacodynamics during bevacizumab treatment as well as the phase I clinical data of CIGB-247, this investigation aims to hypothesize and analyze the potential mechanisms involved in the reduction of platelet-derived free VEGF as a result of vaccination with CIGB-247.Abbreviations: FcγR: Fc gamma receptors; IC: immune complexes; VEGF: vascular endothelial growth factor; VEGFR1: vascular endothelial growth factor receptor 1; VEGFR2: vascular endothelial growth factor receptor 2.