Autologous dendritic cells loaded with antigens from self-renewing autologous tumor cells as patient-specific therapeutic cancer vaccines.

A promising personal immunotherapy is autologous dendritic cells (DC) loaded with autologous tumor antigens (ATA) derived from self-renewing autologous cancer cells. DC-ATA are suspended in granulocyte-macrophage colony stimulating factor at the time of each subcutaneous injection. Previously, irradiated autologous tumor cell vaccines have produced encouraging results in 150 cancer patients, but the DC-ATA vaccine demonstrated superiority in single-arm and randomized trials in metastatic melanoma.

Phase 2 study of AV-GBM-1 (a tumor-initiating cell targeted dendritic cell vaccine) in newly diagnosed Glioblastoma patients: safety and efficacy assessment.

Background: Vaccine immunotherapy may improve survival in Glioblastoma (GBM). A multicenter phase II trial was designed to determine: (1) the success rate of manufacturing the Aivita GBM vaccine (AV-GBM-1), (2) Adverse Events (AE) associated with AV-GBM-1 administration, and (3) survival.

Methods: Fresh suspected glioblastoma tissue was collected during surgery, and patients with pathology-confirmed GBM enrolled before starting concurrent Radiation Therapy and Temozolomide (RT/TMZ) with Intent to Treat (ITT) after recovery from RT/TMZ.

A personal COVID-19 dendritic cell vaccine made at point-of-care: Feasibility, safety, and antigen-specific cellular immune responses.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a world-wide pandemic. Internationally, because of availability, accessibility, and distribution issues, there is a need for additional vaccines. This study aimed to: establish the feasibility of personal dendritic cell vaccines to the SARS-CoV-2 spike protein, establish the safety of a single subcutaneous vaccine injection, and determine the antigen-specific immune response following vaccination.

Cytokine network analysis of immune responses before and after autologous dendritic cell and tumor cell vaccine immunotherapies in a randomized trial.

Background: In a randomized phase II trial conducted in patients with metastatic melanoma, patient-specific autologous dendritic cell vaccines (DCV) were associated with longer survival than autologous tumor cell vaccines (TCV). Both vaccines presented antigens from cell-renewing autologous tumor cells. The current analysis was performed to better understand the immune responses induced by these vaccines, and their association with survival.

Genomic, proteomic, and immunologic associations with a durable complete remission of measurable metastatic melanoma induced by a patient-specific dendritic cell vaccine.

This report describes efforts to understand the immune mechanism of action that led to a complete response in a patient with progressive, refractory, metastatic melanoma after treatment with a therapeutic vaccine consisting of autologous dendritic cells (DC) loaded with autologous tumor antigens (ATA) derived from cells that were self-renewing in cell culture. Her histocompatibility type proved to be HLA B27 with extensive mutations in the HLA-A locus. Exomic analysis of proliferating tumor cells revealed more than 2800 non-synonymous mutations compared to her leukocytes.

Survival Comparison between Melanoma Patients Treated with Patient-Specific Dendritic Cell Vaccines and Other Immunotherapies Based on Extent of Disease at the Time of Treatment.

Encouraging survival was observed in single arm and randomized phase 2 trials of patient-specific dendritic cell vaccines presenting autologous tumor antigens from autologous cancer cells that were derived from surgically resected metastases whose cells were self-renewing in vitro. Based on most advanced clinical stage and extent of tumor at the time of treatment, survival was best in patients classified as recurrent stage 3 without measurable disease. Next best was in stage 4 without measurable disease, and the worst survival was for measurable stage 4 disease.

Preliminary observations on soluble programmed cell death protein-1 as a prognostic and predictive biomarker in patients with metastatic melanoma treated with patient-specific autologous vaccines.

Because of its role as an immune checkpoint, levels of soluble programmed cell death protein-1 (sPD-1) could be useful as a prognostic biomarker or predictive biomarker in cancer patients treated with vaccines. Very low levels of sPD-1 may indicate lack of an existing anti-cancer immune response; very high levels may indicate an active immune response that is suppressed. In between these extremes, a decrease in PD-1 following injections of an anti-cancer vaccine may indicate an enhanced immune response that has not been suppressed.

Patient-specific dendritic cell vaccines with autologous tumor antigens in 72 patients with metastatic melanoma.

Aim: Metastatic melanoma patients were treated with patient-specific vaccines consisting of autologous dendritic cells loaded with antigens from irradiated cells from short-term autologous tumor cell lines.

Patients & Methods: A total of 72 patients were enrolled in a single-arm Phase I/II (NCT00948480) trial or a randomized Phase II (NCT00436930).

Results: Toxicity was minimal.

An update on the relevance of vaccine research for the treatment of metastatic melanoma.

Signal transduction inhibitors and anticheckpoint antibodies have significantly improved survival for metastatic melanoma patients, but most still die within 5 years. Vaccine approaches to induce immunity to well-characterized melanoma-associated antigens, or to antigens expressed on allogeneic tumor cell lines, have not resulted in approved agents. Despite the limitations associated with the immunosuppressive tumor microenvironment, there now is one intralesional autologous vaccine approved for patients who have primarily soft-tissue metastases.

Randomized phase II trial of autologous dendritic cell vaccines versus autologous tumor cell vaccines in metastatic melanoma: 5-year follow up and additional analyses.

Background: Despite improved survival following checkpoint inhibitors, there is still a potential role for anti-cancer therapeutic vaccines. Because of biological heterogeneity and neoantigens resulting from each patient's mutanome, autologous tumor may be the best source of tumor-associated antigens (TAA) for vaccines. Ex vivo loading of autologous dendritic cells with TAA may be associated with superior clinical outcome compared to injecting irradiated autologous tumor cells.

Upfront boost Gamma Knife "leading-edge" radiosurgery to FLAIR MRI-defined tumor migration pathways in 174 patients with glioblastoma multiforme: a 15-year assessment of a novel therapy.

OBJECTIVE Glioblastoma multiforme (GBM) is composed of cells that migrate through the brain along predictable white matter pathways. Targeting white matter pathways adjacent to, and leading away from, the original contrast-enhancing tumor site (termed leading-edge radiosurgery [LERS]) with single-fraction stereotactic radiosurgery as a boost to standard therapy could limit the spread of glioma cells and improve clinical outcomes. METHODS Between December 2000 and May 2016, after an initial diagnosis of GBM and prior to or during standard radiation therapy and carmustine or temozolomide chemotherapy, 174 patients treated with radiosurgery to the leading edge (LE) of tumor cell migration were reviewed.

Dendritic cell vaccines for melanoma: past, present and future.

Administering dendritic cells (DC) loaded with tumor-associated antigens (TAA) is a promising strategy for therapeutic vaccines in advanced melanoma. To date the induction of immune responses to specific TAA has been more impressive than clinical benefit because of TAA limitations, suboptimal DC and possibly immune-checkpoint inhibition. Various products, antigen-loading techniques, treatment schedules, routes of administration and adjunctive agents continue to be explored.

Is there a role for therapeutic cancer vaccines in the age of checkpoint inhibitors?

Because of the recent success of monoclonal antibody checkpoint inhibitors, and the disappointing results of most therapeutic cancer vaccine trials, it has been questioned whether there is any potential role for such products going forward. In my opinion the answer is "yes" based on the following: [1] there is a persistent unmet clinical need because the majority of patients do not benefit from anti-checkpoint therapy, [2] there is evidence that not all patients make immune responses to their tumors, [3] there is evidence that immune responses to autologous tumor antigens can be induced by patient-specific vaccines, [4] there is clinical evidence from the pre-checkpoint era that suggests survival can be positively impacted by such patient-specific vaccines, and [5] the 2 available therapeutic vaccines that have received regulatory approval are quite limited in terms of their therapeutic benefit.

Long-Term Progression-Free and Overall Survival in Two Melanoma Patients Treated with Patient-Specific Therapeutic Vaccine Eltrapuldencel-T After Resection of a Solitary Liver Metastasis.

Hepatic metastases from melanoma are usually associated with recurrence and short survival, even in patients with a solitary metastasis. Two patients, one with melanoma of unknown primary and one with ocular melanoma, underwent resection of a solitary liver metastasis followed by treatment with eltrapuldencel-T, a patient-specific therapeutic vaccine consisting of autologous dendritic cells loaded with antigens from irradiated melanoma cells obtained from an autologous tumor cell line. Following surgical resection, the ocular melanoma patient remained progression free for more than 4.

Dendritic Versus Tumor Cell Presentation of Autologous Tumor Antigens for Active Specific Immunotherapy in Metastatic Melanoma: Impact on Long-Term Survival by Extent of Disease at the Time of Treatment.

In patients with metastatic melanoma, sequential single-arm and randomized phase II trials with a therapeutic vaccine consisting of autologous dendritic cells (DCs) loaded with antigens from self-renewing, proliferating, irradiated autologous tumor cells (DC-TC) showed superior survival compared with similar patients immunized with irradiated tumor cells (TC). We wished to determine whether this difference was evident in cohorts who at the time of treatment had (1) no evidence of disease (NED) or (2) had detectable disease. Eligibility criteria and treatment schedules were the same for all three trials.

Phase I trial of active specific immunotherapy with autologous dendritic cells pulsed with autologous irradiated tumor stem cells in hepatitis B-positive patients with hepatocellular carcinoma.

Background And Objectives: Hepatocellular carcinoma (HCC) is often associated with chronic hepatitis due to hepatitis-B or -C viruses. Active specific immunotherapy (ASI) with autologous dendritic cells (DC) presenting antigens from autologous tumor stem cell (TC) lines is associated with promising long-term survival in metastatic cancer, but hepatitis patients were excluded. ASI might benefit high-risk primary HCC patients following surgical resection, but first it is important to show that ASI does not exacerbate hepatitis.

Cancer vaccines: can they improve survival?

In patients with metastatic cancer, therapeutic anticancer vaccines are rarely associated with objective antitumor responses; so, many investigators have focused on progression-free survival (PFS) as a key endpoint for clinical trials. However, it is not clear that PFS is a surrogate for overall survival (OS), and OS may be a more appropriate endpoint because of the effects on long-term memory in the adaptive immune system. Recently, reported vaccine trials were reviewed to determine their primary and secondary endpoints and results.

Steadily improving survival in lung cancer.

Background: National data demonstrate minimal improvement in survival for patients diagnosed with lung cancer despite a number of apparent advances during the past 3 decades. We wished to know how demographic characteristics, staging, therapy, and survival have changed over time for patients with lung cancer who were accessioned to the cancer registry of a large community hospital in southern California.

Patients And Methods: Clinical features and survival data were collected on patients diagnosed during each of the successive 6-year eras of 1986 to 1991 (n = 812), 1992 to 1997 (n = 1072), 1998 to 2003 (n = 1209), and 2004 to 2009 (n = 1365).

High-dose IL2 in metastatic melanoma: better survival in patients immunized with antigens from autologous tumor cell lines.

Abstract Various published data show that in patients with metastatic melanoma, high-dose interleukin-2 (IL2) is associated with 5-year survival rates of 15% from treatment initiation. We previously reported a median survival of 15.6 months, and a 20% 5-year survival rate for 150 patients who were treated with inpatient IL2 (Cancer Biother Radiopharm 2012;27:337).

Cancer stem cell antigen-based vaccines: the preferred strategy for active specific immunotherapy of metastatic melanoma?

Introduction: There are now two chemotherapy agents, one tyrosine kinase inhibitor and three immunotherapy products approved for the treatment of metastatic melanoma, but an unmet need persists because these options are toxic and of limited therapeutic benefit. Active specific immunotherapy with therapeutic vaccines could be a useful addition to the therapeutic armamentarium, especially in patients whose tumor burden has been reduced by other treatment modalities.

Areas Covered: This article reviews various sources of melanoma antigens, such as peptides, gangliosides, autologous tumor and cancer stem cells including allogeneic and autologous cell lines.