Efficient and persisting immune memory is essential for long-term protection from infectious and malignant diseases. The yellow fever (YF) vaccine is a live attenuated virus that mediates lifelong protection, with recent studies showing that the CD8(+) T cell response is particularly robust. Yet, limited data exist regarding the long-term CD8(+) T cell response, with no studies beyond 5 years after vaccination. We investigated 41 vaccinees, spanning 0.27 to 35 years after vaccination. YF-specific CD8(+) T cells were readily detected in almost all donors (38 of 41), with frequencies decreasing with time. As previously described, effector cells dominated the response early after vaccination. We detected a population of naive-like YF-specific CD8(+) T cells that was stably maintained for more than 25 years and was capable of self-renewal ex vivo. In-depth analyses of markers and genome-wide mRNA profiling showed that naive-like YF-specific CD8(+) T cells in vaccinees (i) were distinct from genuine naive cells in unvaccinated donors, (ii) resembled the recently described stem cell-like memory subset (Tscm), and (iii) among all differentiated subsets, had profiles closest to naive cells. Our findings reveal that CD8(+) Tscm are efficiently induced by a vaccine in humans, persist for decades, and preserve a naiveness-like profile. These data support YF vaccination as an optimal mechanistic model for the study of long-lasting memory CD8(+) T cells in humans.

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Long-lasting stem cell–like memory CD8+ T cells with a naïve-like profile upon yellow fever vaccination

Adoptive cellular therapy (ACT) is a form of immunotherapy whereby antigen-specific T cells are isolated or engineered, expanded ex vivo, and transferred back to patients. Clinical benefit after ACT has been obtained in treatment of infection, various hematological malignancies, and some solid tumors; however, due to poor functionality and persistence of the transferred T cells, the efficacy of ACT in the treatment of most solid tumors is often marginal. Hence, much effort is undertaken to improve T cell function and persistence in ACT and significant progress is being made. Herein, we will review strategies to improve ACT success rates in the treatment of cancer and infection. We will deliberate on the most favorable phenotype for the tumor-specific T cells that are infused into patients and on how to obtain T cells bearing this phenotype by applying novel ex vivo culture methods. Moreover, we will discuss T cell function and persistence after transfer into patients and how these factors can be manipulated by means of providing costimulatory signals, cytokines, blocking antibodies to inhibitory molecules, and vaccination. Incorporation of these T cell stimulation strategies and combinations of the different treatment modalities are likely to improve clinical response rates further.

/pdf/improving-adoptive-t-cell-therapy-the-particular-role-of-t-d1xxgcm59q.pdf

Improving Adoptive T Cell Therapy: The Particular Role of T Cell Costimulation, Cytokines, and Post-Transfer Vaccination

Even though combining surgery with chemotherapy has significantly improved the prognosis of osteosarcoma patients, advanced, metastatic, or recurrent osteosarcomas are often non-responsive to chemotherapy, making development of novel efficient therapeutic methods an urgent need. Adoptive immunotherapy has the potential to be a useful non-surgical modality for treatment of osteosarcoma. Recently, alternative strategies, including immunotherapies using naturally occurring or genetically modified T cells, have been found to hold promise in the treatment of hematologic malignancies and solid tumors. In this review, we will discuss possible T-cell-based therapies against osteosarcoma with a special emphasis on combination strategies to improve the effectiveness of adoptive T cell transfer and, thus, to provide a rationale for the clinical development of immunotherapies.

T-Cell-Based Immunotherapy for Osteosarcoma: Challenges and Opportunities

The practitioners of hostile social manipulation employ social media, sophisticated forgeries, cyberbullying and harassment, distribution of rumors and conspiracy theories, and other tools to cause damage to their target state. This report represents an effort to better define and understand the challenge by focusing on the activities of the two leading authors of such techniques — Russia and China.

/pdf/hostile-social-manipulation-present-realities-and-emerging-cllse8nezo.pdf

Hostile Social Manipulation: Present Realities and Emerging Trends

We examine some problematic narratives in the American international relations scholarship on Russia, focusing on some implicit assumptions about the drivers of Russian foreign policy. Most promine...

The Wilsonian Bias in the Study of Russian Foreign Policy

How to Stand Up to the Kremlin. Defending Democracy Against Its Enemies

The author stresses that the U.S. will remain the world's preeminent power for decades to come due to its investments at home and engagement overseas. He reveals the foundations of U.S. global leadership. The author emphasizes the importance of the Trans-Pacific Partnership. He also discusses the relationship of the U.S. with China.

Joseph R. Biden

Papers

How to Stand Up to the Kremlin. Defending Democracy Against Its Enemies

Building on Success

How to Stand Up to the Kremlin