The multi-specific VH-based Humabody CB213 co-targets PD1 and LAG3 on T cells to promote anti-tumour activity

Background Improving cancer immunotherapy long-term clinical benefit is a major priority. It has become apparent that multiple axes of immune suppression restrain the capacity of T cells to provide anti-tumour activity including signalling through PD1/PD-L1 and LAG3/MHC-II.Methods CB213 has been developed as a fully human PD1/LAG3 co-targeting multi-specific Humabody composed of linked V_H domains that avidly bind and block PD1 and LAG3 on dual-positive T cells. We present the preclinical primary pharmacology of CB213: biochemistry, cell-based function vs. immune-suppressive targets, induction of T cell proliferation ex vivo using blood obtained from NSCLC patients, and syngeneic mouse model anti-tumour activity. CB213 pharmacokinetics was assessed in cynomolgus macaques.Results CB213 shows picomolar avidity when simultaneously engaging PD1 and LAG3. Assessing LAG3/MHC-II or PD1/PD-L1 suppression individually, CB213 preferentially counters the LAG3 axis. CB213 showed superior activity vs. αPD1 antibody to induce ex vivo NSCLC patient T cell proliferation and to suppress tumour growth in a syngeneic mouse tumour model, for which both experimental systems possess PD1 and LAG3 suppressive components. Non-human primate PK of CB213 suggests weekly clinical administration.Conclusions CB213 is poised to enter clinical development and, through intercepting both PD1 and LAG3 resistance mechanisms, may benefit patients with tumours escaping front-line immunological control.Subject terms: Antibody fragment therapy, Cancer immunotherapy, Drug development     

A randomized study of the effectiveness of a brief psychosocial intervention for women attending a gynecologic cancer clinic

ObjectivesWhile there are many psychosocial interventions for cancer patients, few are brief in nature. The aim of this study was to investigate the usefulness of a single-visit psychosocial intervention for gynecologic cancer patients.MethodsOne hundred women attending a gynecologic cancer clinic as new patients were randomized to receive no intervention or a one-time meeting with a psychologist who discussed issues and concerns the woman might have about her cancer diagnosis. Thirty-eight of the women had a current or previous cancer. The women were given questionnaires measuring mood and quality of life at baseline, two weeks and three months after the intervention.ResultsAt baseline, 43 of the women in the control group completed questionnaires, as did 45 women randomized to the intervention. 21 of these women received the intervention. Women who received the intervention had greater decreases in anxiety, depression and overall distress over time. The control group also had decreases in anxiety and overall distress over time, but had an increase in depression. The women in the intervention group increased in physical, emotional, functional, and overall well being, while the control group only had a slight increase in overall well being over time. The difference between the groups in emotional well being at Time 2 approached significance (p = .08). The intervention group had increases in positive coping at Time 2, while the control group decreased (p's ranged from .02–.10). Three month follow-up data were available for 23 women in the control group and 15 in the intervention group. At Time 3 functional well being was significantly higher in the intervention group (p = .04). Information seeking and affect regulation remained higher in the intervention than the control group (p's = .002 and .02, respectively). When the women with cancer or previous cancer were examined, significant differences were seen for affect regulation at baseline (p = .0007), and anger two weeks later (p = .04), with the women in the control group being more angry. Utilization of other cancer resources was low with 12% of the women reporting that they used the Cancer Resource Center.ConclusionsThe results of this study show that there was a positive effect towards coping and quality of life for a one-time psychosocial intervention after the first visit to a gynecologic oncology practice. Women who were randomized to the intervention but did not go were more distressed at baseline than the women who did go. This suggests that incorporating psychosocial services as an integrated part of the new patient consultation may be very important to address patient's distress. Future studies with larger sample sizes may reveal more significant differences. Strategies to overcome the poor utilization of the cancer resource center are also clearly needed to improve awareness of these resources.     

在研新药的安全性,谁来保证

对于已用过所有治疗方法均失败的重症患者，在研新药是他们的一个希望，但是在研新药的安全性如何，已知数据很少。风险和获益两者之间如何把握平衡，对于研发人员来说，这是一个挑战。[编者按]     

Awareness of gynecologic surveillance in women from hereditary non-polyposis colorectal cancer families

Objective To determine knowledge of gynecologic cancer risk and screening in women with HNPCC.Study design Forty-three women with HNPCC were counseled through a gastrointestinal cancer risk program, and later sent a questionnaire regarding their screening practices for gynecologic neoplasms.Results Twenty-seven (63%) of 43 responded. Fifteen (55%) of 27 had previously been diagnosed with cancer. Among 16 women with a uterus, 11 (69%) reported surveillance by ultrasound or endometrial sampling. Among 21 respondents with ovaries, 13 (62%) reported screening by ultrasound or CA125. Twenty-two (81%) of 27 had seen a gynecologist after receiving their HNPCC diagnosis, but only 12% recalled hearing about risks from their gynecologist, and␣8% from their gynecologic oncologist. Genetic counselors were cited as the most common source (48%) of gynecologic cancer risk information.Conclusions While the effectiveness of surveillance remains in question, gynecologists can be a source of information regarding gynecologic cancer risk for women from HNPCC families.Presented at the 10th Biennial International Gynecologic Cancer Society Meeting, October 3–7, 2004, Edinburgh, Scotland     

The place of beta 2 glycoprotein 1 in the assessment of antiphospholipid syndrome.

beta 2 glycoprotein 1 (beta2GP1) is a phospholipid-binding protein implicated in the development of antiphospholipid antibodies, associated with thromboembolic complications and fetal morbidity and death, and is thought to corrrelate better than anticardiolipin (aCL) assays. We analysed the role of beta2GP1 in assessing 86 patients being investigated for antiphospholipid syndrome. Thirty-nine patients had 3 tests: [lupus anticoagulant (LA), aCL and beta2GP1], and a further 46 had aCL and beta2GP1. Sixty-one patients had completely negative tests. Five patients had beta2GP1 as the only positive result. 80% of this group had recurrent miscarriage suggesting that beta2GP1 may be an useful adjunct to aCL and LA testing in patients with a significant obstetric history.     

Antiarrhythmics in atrial fibrillation

Atrial fibrillation (AF) is a common arrhthymia that exists in both the acute and chronic form. As the molecular basis of arrhythmogenesis is further elucidated, the discovery of novel antiarrhythmic agents, which can be tailored to individual patients and the particular subtype of AF, while minimizing potential side effects, will become possible.     

The psychological impact of mammographic screening on women with a family history of breast cancer--a systematic review

This systematic review aims to assess the psychological impact of mammographic screening on women with a family history of breast cancer. Women with a family history, and hence increased risk, of breast cancer are known to experience higher levels of anxiety about cancer. They are also often offered screening from an earlier age. The psychological consequences of screening are therefore of particular importance for this group of women. A comprehensive search of 4 electronic databases was conducted from 1982 to 2003, combining sets of terms relating to (1) breast screening or mammography (breast screen*; mammogra*), (2) psychological impact (adverse effects; anxi*; distress; nervous; psych*, psychological consequences; stress; worry) and (3) family history. Reference lists from relevant papers were examined for additional papers. The review identified seven papers from four countries. Overall, the findings indicate that, similar to women in the general population, most women with a family history do not appear to experience high levels of anxiety associated with mammographic screening. Although women who are recalled for further tests do experience increased anxiety the levels appear to be no greater than for women without a family history. We conclude that further research on this topic is required--this should include studies designed specifically to consider both the negative and positive impact of mammographic screening on women with a family history, using validated measures of anxiety and worry in combination with qualitative research.