This article summarizes key review findings that supported the approval of tocilizumab for treatment of severe or life‐threatening CAR T cell‐induced cytokine release syndrome.
The online version of this article has a Supplementary Appendix. BackgroundWe previously showed that vaccination with one dose of PR1 and WT1 peptides induces transient anti-leukemia immunity. We hypothesized that maintenance of a sustained anti-leukemia response may require frequent boost injections. Design and MethodsEight patients with myeloid malignancies were enrolled in this phase II study, and 6 completed 6 injections of PR1 and WT1 peptides in Montanide-adjuvant with GM-CSF, every two weeks. ResultsBoth high-and low-avidity PR1 or WT1-specific CD8 + T cells were detected in all evaluable patients after the first vaccine dose. Repeated vaccination led to selective deletion of high avidity PR1-and WT1-specific CD8 + T cells and was not associated with significant reduction in WT1-expression. Additional boosting failed to increase vaccine-induced CD8 + T-cell frequencies further and in all patients the response was lost before the 6 th dose. PR1-or WT1-specific CD8 + T cells were not detected in bone marrow samples, excluding their preferential localization to this site. Following a booster injection three months after the 6 th vaccine dose, no highavidity PR1 or WT1-specific CD8 + T cells could be detected, whereas low-avidity T cells were readily expanded. ConclusionsThese data support the immunogenicity of PR1 and WT1 peptide vaccines. However, repeated delivery of peptides with Montanide-adjuvant and GM-CSF leads to rapid loss of high-avidity peptide-specific CD8 + T cells. These results may offer an explanation for the lack of correlation between immune and clinical responses observed in a number of clinical trials of peptide vaccination. New approaches are needed to induce long-term high-avidity memory responses against leukemia antigens.
Immune reconstitution following hematopoietic stem cell transplantation (HCT) beyond one year is not completely understood. Many transplant recipients who are free of graft versus host disease (GVHD) and not receiving any immunosuppression more than a year after transplant seem to be able to mount appropriate immune responses to common pathogens and respond adequately to immunizations. However, two large registry studies over the last two decades seem to indicate that infection is a significant cause of late mortality in some patients, even in the absence of concomitant GVHD. Research on this topic is particularly challenging for several reasons. First, there are not enough long term follow-up clinics able to measure even basic immune parameters late after HCT. Second, the correlation between laboratory measurements of immune function and infections is not well known. Third, accurate documentation of infectious episodes is notoriously difficult. Finally, it is unclear what measures can be implemented to improve the immune response in a clinically relevant way. A combination of long-term multicenter prospective studies that collect detailed infectious data and store samples as well as a national or multi-national registry of clinically significant infections (e.g., vaccine-preventable severe infections, opportunistic infections) could begin to address our knowledge gaps. Obtaining samples for laboratory evaluation of the immune system should be both calendar driven and eventdriven. Attention to detail and standardization of practices regarding prophylaxis, diagnosis and definitions of infections would be of paramount importance to obtain clean, reliable data. Laboratory studies should specifically address the neogenesis, maturation and exhaustion of the adaptive immune system and in particular how these are influenced by persistent alloreactivity, inflammation and viral infection. Ideally, some of these long-term prospective studies would collect information on long-term changes in the gut microbiome and their influence on immunity. Regarding enhancement of immune function, prospective measurement of the response to vaccines late after HCT in a variety of clinical settings should be undertaken to better understand the benefit as well as the limitations of immunizations. The role of intravenous immunoglobulin is still not well defined, and studies to address it should be encouraged.
Allogeneic hematopoietic stem cell transplantation (SCT) is a curative treatment for some hematological malignancies. As the overall number of survivors continues to increase, studies systematically examining outcomes in long-term survivors are needed. We studied the clinical and quality of life outcomes in SCT recipients surviving five or more years from SCT. Since 1993, 262 patients with hematological malignancies received a T cell depleted myeloablative SCT from an HLA-identical sibling at a single center. Ninety-two survived beyond 5 years from SCT (median follow-up 9.4 years, range 5.1-15.3). Median age at transplantation was 35 years (range 10 - 56). Twenty-two (24%) received a bone marrow transplant, and 70 (76%) received a peripheral blood SCT. Of the 92 survivors, 60 completed quality of life measures. The main outcomes examined were chronic graft-versus-host-disease (cGVHD), disease relapse, survival, health-related quality of life (HRQL) (Functional Assessment of Cancer Therapy-General), physical and mental health (SF-36) and symptom experience (Rotterdam Symptom Checklist). Seventy-five (82%) of 92 survivors no longer required systemic immunosuppressive treatment (IST). Four (4.3%) relapsed with leukemia at a median of 8.5 years (range 6.2 -14.0) after SCT. Four (4.3%) died between 7.4 and 13.4 years post SCT (1 relapse, 1 lung cancer, 1 pneumonia, 1 brain hemorrhage). Most survivors beyond 5 years had an excellent performance status with no difference in physical and mental health and higher HRQL scores (p =0.02) compared with population norms. Although physical and psychological symptom distress was low, those with higher symptom distress experienced inferior HRQL. These results show that five or more years after T cell depleted SCT for hematological malignancy most individuals survive disease free with an excellent performance status, preserved physical and psychological health, and excellent HRQL.
Long term survivors of allo-SCT have increased risk of cardiovascular disease. We retrospectively studied cardiovascular risk factors (CVRF) in 109 SCT survivors (62 males, 47 females; median age 34 years) ≥5 years after bone-marrow (15) or T-cell-depleted peripheral blood (94) SCT for CML (56), acute leukemia (29), MDS (13), and others (11). One death and 2 cardiovascular events were reported. At 5 and 10 years post-SCT respectively, 44% and 52% had abnormal lipid profiles. 23% of 5-year survivors met the Adult Treatment Panel III threshold for dyslipidemia treatment, which is substantially higher than the age-matched general population. There were significant increases in prevalence of hypertension (p<0.001), diabetes (p=0.018) and body mass index (p=0.044) post-SCT compared to baseline. The Framingham general cardiovascular risk score (FGCRS) in males at 5 years post-SCT projected a doubling (median 10.4% vs. 5.4%) in the 10-year risk of cardiovascular events. Females received HRT post-SCT and none had increased FGCRS. Chronic GVHD and C-reactive protein were not associated with CVRF at any time point. All CVRF stabilized between 5 and 10 years post-SCT. Thus, SCT survivors have sustained elevations in CVRF. Males have a significantly increased risk of cardiovascular events in their second and third decade post-SCT.
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