Next-generation cancer vaccines and emerging immunotherapy combinations.

Therapeutic cancer vaccines have been a subject of research for several decades as potential new weapons to tackle malignancies. Their goal is to induce a long-lasting and efficient antitumour-directed immune response, capable of mediating tumour regression, preventing tumour progression, and eradicating minimal residual disease, while avoiding major adverse effects. Development of new vaccine technologies and antigen prediction methods has led to significant improvements in cancer vaccine efficacy. However, for their successful clinical application, certain obstacles still need to be overcome, especially tumour-mediated immunosuppression and escape mechanisms. In this review, we introduce therapeutic cancer vaccines and subsequently discuss combination approaches of next-generation cancer vaccines and existing immunotherapies, particularly immune checkpoint inhibitors (ICIs) and adoptive cell transfer/cell-based immunotherapies.

Rapid protection against viral infections by chemokine-accelerated post-exposure vaccination.

Introduction: Prophylactic vaccines generate strong and durable immunity to avoid future infections, whereas post-exposure vaccinations are intended to establish rapid protection against already ongoing infections. Antiviral cytotoxic CD8+ T cells (CTL) are activated by dendritic cells (DCs), which themselves must be activated by adjuvants to express costimulatory molecules and so-called signal 0-chemokines that attract naive CTL to the DCs. Hypothesis: Here we asked whether a vaccination protocol that combines two adjuvants, a toll-like receptor ligand (TLR) and a natural killer T cell activator, to induce two signal 0 chemokines, synergistically accelerates CTL activation. Methods: We used a well-characterized vaccination model based on the model antigen ovalbumin, the TLR9 ligand CpG and the NKT cell ligand α-galactosylceramide to induce signal 0-chemokines. Exploiting this vaccination model, we studied detailed T cell kinetics and T cell profiling in different in vivo mouse models of viral infection. Results: We found that CTL induced by both adjuvants obtained a head-start that allowed them to functionally differentiate further and generate higher numbers of protective CTL 1-2 days earlier. Such signal 0-optimized post-exposure vaccination hastened clearance of experimental adenovirus and cytomegalovirus infections. Conclusion: Our findings show that signal 0 chemokine-inducing adjuvant combinations gain time in the race against rapidly replicating microbes, which may be especially useful in post-exposure vaccination settings during viral epi/pandemics.

Case report: Ipilimumab and nivolumab in metastatic adrenocortical cancer with high tumor mutational burden.

In the setting of metastatic adrenocortical cancer, there are limited therapy options such as mitotane and platinum-based chemotherapy with only low response rates. Ipilimumab and nivolumab are approved for several solid cancer types. Tumor mutational burden is one established marker to predict treatment success of immunotherapy and has been associated with improved response rates to immune checkpoint inhibitors. We here present the case of a 68-year-old woman with metastatic adrenocortical cancer and high tumor mutational burden treated with ipilimumab and nivolumab in a fourth-line setting. She showed a stable disease for at least 48 weeks, which is significantly longer than the treatment response to mitotane or platinum-based chemotherapy. To the best of our knowledge, this is the first successful use of a long-term two-drug immunotherapy (48 weeks) in a patient with metastatic adrenocortical cancer and high mutational burden. Ipilimumab and nivolumab should be considered as a new therapy option in this patient group.

Severe autoimmune hemolytic anemia following immunotherapy with checkpoint inhibitors in two patients with metastatic melanoma: a case report.

Introduction: Over the past decade, immune checkpoint inhibitors such as antibodies against cytotoxicity T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) have become an important armamentarium against a broad spectrum of malignancies. However, these specific inhibitors can cause adverse autoimmune reactions by impairing self-tolerance. Hematologic side effects of immune checkpoint inhibitors, including autoimmune hemolytic anemia (AIHA), are rare but can be life-threatening. Case report: Herein, we report two patients on immune checkpoint inhibitors for metastatic melanoma who developed AIHA with symptoms of dyspnea and fatigue. In the first patient, symptoms alleviated after discontinuation of combined anti CTLA-4 and anti-PD-1 therapy, initiation of corticosteroids and application of a single red blood cell transfusion. Due to subsequent progress of melanoma, combinational anti-PD-1 and tyrosine kinase inhibitor therapy was initiated based on multidisciplinary tumor board decision. After two months, she again developed the described hematological and clinical signs of AIHA leading to cessation of anti-PD-1 therapy and initiation of corticosteroids, which again resulted in an alleviation of her symptoms. Due to further progression, the patient received dacarbazine for several months before she decided to stop any therapy other than palliative supportive care. In the second patient, discontinuation of anti-PD-1 therapy and initiation of corticosteroids entailed a complete alleviation of his symptoms. After refusing chemotherapy due to subsequent melanoma progression, he received radiotherapy of bone metastases and is currently enrolled in a clinical trial. The patient did not develop AIHA ever since. Conclusion: Hematologic immune-related adverse events due to treatment with immune checkpoint inhibitors are rare but can have life-threatening consequences. If dyspnea and other clinical symptoms are present, AIHA should be considered as a potential cause and treated promptly in a multidisciplinary setting. An expanded comprehension of risk factors and pathogenesis of AIHA is needed to identify high-risk patients beforehand, leading to more effective predictive and reactive treatment approaches.