Humoral immunity against SARS-CoV-2 variants including omicron in solid organ transplant recipients after three doses of a COVID-19 mRNA vaccine.

Objectives: Solid organ transplant recipients (SOTR) receiving post-transplant immunosuppression show increased COVID-19-related mortality. It is unclear whether an additional dose of COVID-19 vaccines can overcome the reduced immune responsiveness against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. Methods: We analysed humoral immune responses against SARS-CoV-2 and its variants in 53 SOTR receiving SARS-CoV-2 vaccination. Results: Following the initial vaccination series, 60.3% of SOTR showed no measurable neutralisation and only 18.9% demonstrated neutralising activity of > 90%. More intensive immunosuppression, antimetabolites in particular, negatively impacted antiviral immunity. While absolute IgG levels were lower in SOTR than controls, antibody titres against microbial recall antigens were higher. By contrast, SOTR showed reduced vaccine-induced IgG/IgA antibody titres against SARS-CoV-2 and its delta variants and fewer linear B-cell epitopes, indicating reduced B-cell diversity. Importantly, a third vaccine dose led to an increase in anti-SARS-CoV-2 antibody titres and neutralising activity across alpha, beta and delta variants and to the induction of anti-SARS-CoV-2 CD4+ T cells in a subgroup of patients analysed. By contrast, we observed significantly lower antibody titres after the third dose with the omicron variant compared to the ancestral SARS-CoV-2 and the improvement in neutralising activity was much less pronounced than for all the other variants. Conclusion: Only a small subgroup of solid organ transplant recipients is able to generate functional antibodies after an initial vaccine series; however, an additional vaccine dose resulted in dramatically improved antibody responses against all SARS-CoV-2 variants except omicron where antibody responses and neutralising activity remained suboptimal.

Deep dissection of the antiviral immune profile of patients with COVID-19.

In light of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variants potentially undermining humoral immunity, it is important to understand the fine specificity of the antiviral antibodies. We screened 20 COVID-19 patients for antibodies against 9 different SARS-CoV-2 proteins observing responses against the spike (S) proteins, the receptor-binding domain (RBD), and the nucleocapsid (N) protein which were of the IgG1 and IgG3 subtypes. Importantly, mutations which typically occur in the B.1.351 "South African" variant, significantly reduced the binding of anti-RBD antibodies. Nine of 20 patients were critically ill and were considered high-risk (HR). These patients showed significantly higher levels of transforming growth factor beta (TGF-ß) and myeloid-derived suppressor cells (MDSC), and lower levels of CD4+ T cells expressing LAG-3 compared to standard-risk (SR) patients. HR patients evidenced significantly higher anti-S1/RBD IgG antibody levels and an increased neutralizing activity. Importantly, a large proportion of S protein-specific antibodies were glycosylation-dependent and we identified a number of immunodominant linear epitopes within the S1 and N proteins. Findings derived from this study will not only help us to identify the most relevant component of the anti-SARS-CoV-2 humoral immune response but will also enable us to design more meaningful immunomonitoring methods for anti-COVID-19 vaccines.

Anti-SARS-CoV-2 Immune Responses in Patients Receiving an Allogeneic Stem Cell or Organ Transplant.

Patients after autologous (autoSCT) and allogeneic stem cell transplantation (alloSCT) are at an increased risk of COVID-19-related morbidity and mortality, compounded by an immune system weakened by the underlying malignancy and prior treatments. Allogeneic transplantation, including stem cell and solid organ transplants, requires intensive immunosuppressive prophylaxis, which may further undermine the development of a protective vaccine-induced anti-viral immunity. Herein, we report on short- and long-term antiviral immune responses in two peri-stem cell transplant recipients and a third patient who received a COVID-19 vaccination after kidney transplantation. Our data indicate that: (1) patients post-alloSCT may be able to mount an anti-COVID-19 immune response; however, a sufficient time interval between transplant and exposure may be of critical importance; (2) alloSCT recipients with preexisting anti-SARS-CoV-2 immunity are at risk for losing protective humoral immunity following transplantation, particularly if the stem-cell donor lacks antiviral immunity, e.g., vaccine-derived immunity; and (3) some post-transplant patients are completely unable to build an immune response to a COVID-19 vaccine, perhaps based on the prophylactic suppression of T cell immunity.

Update on testicular germ cell tumors.

PURPOSE OF REVIEW: This overview discusses several important developments in testicular germ cell tumors (TGCTs) over the past year. RECENT FINDINGS: Genomic studies continue to investigate gene expression as possible markers for disease relapse and metastatic potential. Optimal treatment strategies for early-stage seminomas continue to evolve toward surveillance versus chemotherapy, although developing radiation delivery modalities may ultimately provide a safe alternative. The role of retroperitoneal lymph node dissection in postorchiectomy early-stage nonseminoma germ cell tumors remains a topic of debate. SUMMARY: Treatment paradigms continue to be refined for TGCTs as research in these areas continues.

Testicular germ cell tumors: biology and clinical update.

PURPOSE OF REVIEW: To discuss several important developments in the diagnosis, management, and risk stratification of testicular germ cell tumors (TGCTs) in the past year. RECENT FINDINGS: Germ cell function and tumorigenesis may be influenced by exposure to a variety of agents, including metals and cannabinoids. Genome-wide association studies have identified variants in several genes that may produce susceptibility to the development of testicular malignancies, and expression of certain proteins predicts a poorer prognosis and may, thus, play a role in neoplastic progression. Retroperitoneal lymph node dissection continues to play a crucial role in definitive treatment of patients with nonseminoma germ cell tumor, whereas radiotherapy, as a standard treatment for early-stage seminoma, has been declining due both to the efficacy of platinum-based chemotherapy and to the increased risk of radiation-related secondary malignancies. Advanced and platinum-refractory disease states continue to be challenging entities in terms of optimizing therapy and outcome. SUMMARY: Preclinical and clinical studies continue to enhance our insights into the complex biology of TGCTs, and are helping to further refine risk stratification and optimize treatment of patients with TGCTs.

Testicular germ cell tumors: biology and clinical update.

PURPOSE OF REVIEW: This overview discusses several important developments in testicular germ cell tumors in the past year. RECENT FINDINGS: Genomic studies continue to investigate gene expression as possible markers for disease relapse and chemotherapy resistance. Optimal treatment strategies for early-stage seminomas are evolving toward surveillance versus chemotherapy and away from radiation, and the role of retroperitoneal lymph node dissection in disseminated nonseminomatous cancers in complete remission is becoming less certain. SUMMARY: Treatment and surveillance paradigms continue to be defined and refined for both early and late-stage disease as research in these areas continues and the data from multiple large studies mature.

Update on testicular germ cell tumors.

PURPOSE OF REVIEW: This overview discusses several important developments in testicular germ cell tumors in the last year. RECENT FINDINGS: Genomic studies are examining gene expression as possible markers for disease relapse and chemotherapy resistance. Optimal treatment strategies for early-stage nonseminomatous tumors continue to evolve, and advanced disease states continue to be challenging entities in terms of optimizing therapy and outcome. Long-term survivorship issues are also being evaluated in this patient population. SUMMARY: Significant challenges remain for treatment of certain categories of testicular germ cell tumors. Treatment and surveillance paradigms continue to be defined and refined as research in these areas continues.

Update on testicular germ cell tumors.

PURPOSE OF REVIEW: To discuss several important developments in testicular germ cell tumors in the past year. RECENT FINDINGS: Genomic studies are examining gene expression as possible markers for disease relapse and chemotherapy resistance. Optimal treatment strategies for early-stage nonseminomatous tumors continue to evolve and patient compliance with posttreatment surveillance schedules remains problematic. Advanced and platinum-refractory disease states continue to be challenging entities in terms of optimizing therapy and outcome. SUMMARY: Significant challenges remain for treatment of certain categories of testicular germ cell tumors. Treatment and surveillance paradigms continue to be defined and refined as research in these areas continues.

Update on testicular germ cell tumors.

PURPOSE OF REVIEW: This overview discusses several important developments in testicular germ cell tumors in the past year. RECENT FINDINGS: Genomic studies are examining gene expression as possible markers for disease relapse and chemotherapy resistance. Optimal posttreatment surveillance strategies continue to evolve. Retroperitoneal lymph node dissection remains a prominent treatment modality, although the sequencing and extent of surgical intervention is controversial. Platinum-based chemotherapy remains the gold standard for treatment of systemic disease. Poor risk, platinum-refractory and late relapse disease states continue to be challenging entities in terms of optimizing therapy and outcome. SUMMARY: Significant challenges remain for treatment of certain categories of testicular germ cell tumors. Treatment and surveillance paradigms continue to be defined and refined as research in these areas continues.

Evolving role of surgery, radiation, hormone therapy, and chemotherapy in high-risk locally advanced prostate cancer.

Locally advanced prostate cancer encompasses several disease states that vary in the risk for progression and recurrence after initial treatment. Further, the optimal treatment strategies for locally advanced prostate cancer are continuing to evolve, reflecting the complex nature of this disease state. For many patients, clinical experience demonstrates that a combined approach of locally directed therapy and systemic therapy is likely to provide better long-term outcome than single-modality therapy. Randomized studies have established hormone ablation with external-beam radiation as an important form of treatment for this group of patients. However, additional progress needs to be made, particularly in the subgroup of patients with very high-risk disease features. As the optimal integration of local and systemic treatments becomes more clearly defined, the long-term prognosis for patients with high-risk locally advanced prostate cancer will improve.

What constitutes high-risk locally advanced prostate cancer?

Excluding basal and squamous cell cancers of the skin, prostate cancer is the most common malignancy diagnosed in the United States. With increasing awareness and routine prostate-specific antigen testing, a remarkable migration in the clinical presentation of the disease has occurred in the past 20 years. An increasingly greater proportion of men are diagnosed with clinically organ-confined disease. In parallel, the incidence of men presenting with clinically bulky locoregional or metastatic disease has decreased. Despite the stage migration, when clinical and pathologic parameters are taken into account, a significant number of men with clinically localized prostate cancer do not have truly organ-confined disease. Such men might not to be cured with single modality, locally directed therapies. Thus, prostate cancer represents a disease spectrum with a number of biologic and clinical factors determining disease extent. An overview of some of these aspects of the disease is presented.