Large-scale group genetic counseling: Evaluation of a novel service delivery model in a Canadian hereditary cancer clinic.

Increasing demand for genetic services has led to the development of streamlined genetic counseling (GC) models. We piloted large-scale group pre-test GC with up to 50 patients per group and compared this to a traditional one-on-one approach. Patients referred to the British Columbia (BC) Cancer Hereditary Cancer Program were eligible if they had: (a) family history meeting our program's referral criteria; (b) no relevant personal history of cancer; (c) no prior genetic testing in the family; and (d) no living testable relative in BC. Patient-reported outcome measures included: (a) Genetic Counselling Outcome Scale (GCOS) prior to pre-test GC (T1) and at 4 weeks post-test GC (T2); (b) Satisfaction Survey after pre-test GC; and (c) the Multidimensional Impact of Cancer Risk Assessment (MICRA) for patients undergoing testing (4 weeks after post-test GC). In total, 391 patients underwent GC, 184 by group and 207 by one-on-one appointments. Between May 2018 and May 2019, 6 pre-test group sessions were conducted (median number of patients per group = 28; range 15-48). 8% of patients (n = 32) declined large group GC due to personal preference for one-on-one GC. There were no statistically significant differences in MICRA and GCOS survey results when comparing the pre-test large group versus traditional pre-test one-on-one models (based on 3 MICRA subscales: p = 0.063, p = 0.612, p = 0.842; and GCOS p = 0.169). Overall, the large group pre-test counseling approach was more time-efficient with 15-48 patient group sessions conducted over a mean duration of 80 min as compared to 42 min per patient with the traditional one-on-one GC model. Large-scale group GC was feasible and acceptable to patients and represents a novel streamlined model for GC to enable timely access to cancer genetic services.

A Cross-Reactive Small Protein Binding Domain Provides a Model to Study Off-Tumor CAR-T Cell Toxicity.

Tumor-targeted chimeric antigen receptor (CAR)-engineered T lymphocytes (CAR-T cells) have demonstrated striking clinical success, but their use has been associated with a constellation of toxicities. A better understanding of the pathogenesis of these toxicities is required to improve the safety profile of CAR-T cells. Herein, we describe a xenograft model of off-tumor CAR-T cell-associated toxicity. Human CAR-T cells targeted against HER2 using a small-protein binding domain induced acute, dose-dependent toxicities in mice. The inclusion of a CD28 or 4-1BB co-stimulatory domain in the CAR was required to produce toxicity; however, co-stimulation through CD28 was most toxic on a per-cell basis. CAR-T cell activation in the lungs and heart was associated with a systemic cytokine storm. The severity of observed toxicities was dependent upon the peripheral blood mononuclear cell (PBMC) donor used as a T cell source and paralleled the CD4+-to-CD8+ T cell ratio in the adoptive transfer product. CD4+ CAR-T cells were determined to be the primary contributors to CAR-T cell-associated toxicity. However, donor-specific differences persisted after infusion of a purified CD4+ CAR-T cell product, indicating a role for additional variables. This work highlights the contributions of CAR-T cell-intrinsic variables to the pathogenesis of off-tumor toxicity.

Molecular Subtype Not Immune Response Drives Outcomes in Endometrial Carcinoma.

PURPOSE: Tumors with high mutation load are thought to engender stronger immune responses, which in turn promote prolonged patient survival. To investigate this, we assessed tumor-infiltrating lymphocytes (TILs) and immunosuppressive factors across the 4 molecular subtypes of endometrial cancer, which have characteristic mutation rates ranging from low to ultra-high. EXPERIMENTAL DESIGN: A total of 460 endometrial cancers were stratified by ProMisE (Proactive Molecular Risk Classifier in Endometrial cancer) into 4 molecular subtypes: mismatch repair-deficient (MMRd), POLE mutant (POLE), p53 abnormal (p53abn), and p53 wild-type (p53wt). Immune markers (CD3, CD8, CD79a, CD138, PD-1, PD-L1, FoxP3, IDO-1) were quantified by multiplex IHC and tested for associations with ProMisE subtype, survival, and other clinicopathologic parameters. RESULTS: Two major TIL patterns were observed. TILhigh tumors harbored dense T- and B-lineage infiltrates and multiple immunosuppressive features and were common in molecular subtypes associated with high mutation load (MMRd and POLE); however, equally strong responses were seen in significant numbers of p53abn and p53wt tumors, which have characteristically low mutation loads. TILlow tumors were generally devoid of immunologic features and were more prevalent in p53abn and p53wt endometrial cancers, yet were also seen in MMRd and POLE subtypes. In multivariable models involving ProMisE subtype, T-cell markers, and TIL clusters, only ProMisE showed independent prognostic significance. CONCLUSIONS: Immune response correlates with endometrial cancer molecular subtype but does not carry independent prognostic significance. Profound variation in immune response is seen across and within endometrial cancer molecular subtypes, suggesting that assessment of immune response rather than molecular subtype may better predict response to immunotherapy.See related commentary by Mullen and Mutch, p. 2366.

The chimeric TAC receptor co-opts the T cell receptor yielding robust anti-tumor activity without toxicity.

Engineering T cells with chimeric antigen receptors (CARs) is an effective method for directing T cells to attack tumors, but may cause adverse side effects such as the potentially lethal cytokine release syndrome. Here the authors show that the T cell antigen coupler (TAC), a chimeric receptor that co-opts the endogenous TCR, induces more efficient anti-tumor responses and reduced toxicity when compared with past-generation CARs. TAC-engineered T cells induce robust and antigen-specific cytokine production and cytotoxicity in vitro, and strong anti-tumor activity in a variety of xenograft models including solid and liquid tumors. In a solid tumor model, TAC-T cells outperform CD28-based CAR-T cells with increased anti-tumor efficacy, reduced toxicity, and faster tumor infiltration. Intratumoral TAC-T cells are enriched for Ki-67+ CD8+ T cells, demonstrating local expansion. These results indicate that TAC-T cells may have a superior therapeutic index relative to CAR-T cells.

PD-L1 and intratumoral immune response in breast cancer.

PURPOSE: PD-L1 is thought to play an important role in the antitumor immune response. In this study, we investigated the expression of PD-L1 within breast tumor subsets to better define its prognostic significance. METHODS: Immunohistochemistry was performed to determine PD-L1 tumor cell expression and to enumerate CD8, CD4 and CD68 tumor-infiltrating leucocytes (TIL) in a cohort of 443 breast cancers categorized by molecular subtype. RESULTS: Across the entire cohort, PD-L1 tumor cell expression was observed in 73/443 (16.5%) cases and associated with known indicators of poor prognosis, including low patient age, high tumor grade, ER/PR negative status, but not with outcome. However, in the Triple Negative breast cancer subset PD-L1 was associated with better recurrence free survival (RFS) especially within the Basal-like subset (Hazard ratio = 0.39, 95% CI = 0.22 - 0.86, p = 0.018). Combined PD-L1/epithelial CD8 positive status was also strongly associated with better RFS and OS (Hazard ratio = 0.12, 95% CI = 0.10 - 0.71, p = 0.010 and Hazard ratio = 0.11, 95% CI = 0.11 - 0.68, p = 0.006 respectively) in the Basal-like subgroup. CONCLUSIONS: PD-L1 expression is associated with better patient survival in Basal-like breast cancer.

CD103 and Intratumoral Immune Response in Breast Cancer.

PURPOSE: CD103 is expressed in several immune cell types but in the context of the intratumoral immune response may be most important as a marker of antigen-activated CD8 T cells. METHODS: We have examined the prognostic significance of CD103 TILs in breast cancer by IHC in a cohort of 424 breast cancer patients. RESULTS: CD103 TILs were present in all subtypes but were more abundant in ER-negative tumors where CD103 TILs were preferentially localized to the intraepithelial compartment. CD103 was associated with tumor size, tumor grade, and ER/PR status (P < 0.05). CD103 TIL density and the epithelial to stromal ratio was highest in the basal-like tumors. Intraepithelial CD103 but not intrastromal CD103 was associated with better relapse-free and overall survival in basal-like subtype tumors [HR = 0.28; 95% confidence interval (CI), 0.17-0.72; P = 0.0047 and HR = 0.25; 95% CI, 0.17-0.66; P = 0.0017, respectively). CD8 status showed similar but less significant associations, but the combination of dual CD103+CD8+ TIL status was the most strongly prognostic combination for relapse-free and overall survival (HR = 0.10; 95% CI, 0.07-0.62; P = 0.006 and HR = 0.09; 95% CI, 0.07-0.57; P = 0.003, respectively). CONCLUSIONS: CD103 TILs are indicative of a good prognosis specifically within the basal-like subtype of breast cancer. Clin Cancer Res; 22(24); 6290-7. ©2016 AACR.