Generating CAR T cells from tumor-infiltrating lymphocytes.

Background: Tumor-infiltrating lymphocytes (TILs) and chimeric antigen receptor (CAR) T-cell therapies have demonstrated promising, though limited, efficacy against melanoma. Methods: We designed a model system to explore the efficacy of dual specific T cells derived from melanoma patient TILs by transduction with a Her2-specific CAR. Results: Metastatic melanoma cells in our biobank constitutively expressed Her2 antigen. CAR-TIL produced greater amounts of IFN compared with parental TIL, when co-cultured with Her2 expressing tumor lines, including autologous melanoma tumor lines, although no consistent increase in cytotoxicity by TIL was afforded by expression of a CAR. Results of an in vivo study in NSG mice demonstrated tumor shrinkage when CAR-TILs were used in an adoptive cell therapy protocol. Conclusion: Potential limitations of transduced TIL in our study included limited proliferative potential and a terminally differentiated phenotype, which would need addressing in further work before consideration of clinical translation.

Abnormal screens among nonmutation carriers in the High Risk Ontario Breast Screening Program.

BACKGROUND: The Ontario Breast Screening Program was expanded in 2011 to offer annual MRI and mammography to women with high-risk genetic mutations (e.g., BRCA1/2) and women with strong family histories and ≥25% estimated lifetime risk of breast cancer. Data to support high-risk screening is less clear in the nonmutation carrier group, as MRI has lower specificity among this population. The potential unintended consequences may be considerable and need to be explored. We aimed to describe the frequency of abnormal screens and biopsies. METHODS: Demographic surveys and chart review consent were sent to a sample of 441 individuals enrolled in a high-risk screening program at two tertiary care hospitals in Toronto, Ontario. Retrospective cross-sectional chart review was undertaken for clinicopathologic data. The frequencies of abnormal screens and biopsies were calculated. RESULTS: One hundred sixty-nine nonmutation carriers were included. The majority were white, employed, and highly educated. The median International Breast Cancer Intervention Study lifetime risk of breast cancer was 28.0% (range 24.5%-89.0%). 108 individuals (64%) experienced at least 1 abnormal screen and 13 (8%) had 3 or more over a median 3 years of screening (range 1-6 years). Of 55 biopsies, 3 (5.5%) were malignant. The cancer detection rate was 8.4/1000 screens (95% CI 3.2-22.4). CONCLUSIONS: An MRI-based screening program for nonmutation carriers was effective at diagnosing breast cancer. However, this population experienced a high rate of abnormal screens and intervention. Further research is needed to improve the performance of MRI-based screening in these women.

Oncocytic subtypes of adrenal cortical carcinoma: Aggressive in appearance yet more indolent in behavior?

BACKGROUND: Adrenal cortical carcinoma is an aggressive malignancy and typically heralds a poor prognosis. The oncocytic subtype of this neoplasm is rare but may be associated with more favorable outcomes. METHODS: The Provincial Cancer Registry was searched for cases of adrenal cortical carcinoma between 1992 and 2017. Comprehensive chart reviews were performed and data gathered related to presentation, treatment, and outcomes. RESULTS: In the study, 82 patients with adrenal cortical carcinoma were identified. Complete data were available for 67 patients (82%). In the 41 patients who underwent resection, 9 (22%) had oncocytic subtypes. When compared with the total group of adrenal cortical carcinomas, the oncocytic subtypes were larger at presentation (19.8 cm vs 11.0 cm), more commonly symptomatic and hormonally active, and despite larger tumor size, were often early stage I and II. Recurrent disease was observed in 3 out of 9 oncocytic subtype (vs 23 out of 32 adrenal cortical carcinoma), with greater median time to recurrence (17.5 vs 8 months). Univariate analysis suggested that age, T-stage, M-stage, and overall stage were associated with survival. There was a trend toward improved overall survival for patients with oncocytic subtype on Kaplan-Meier and multivariate analysis. CONCLUSION: Despite our small numbers of patients with oncocytic subtype, our data suggest that oncocytic subtype are typically larger at presentation but more often early stage and recur less frequently than adrenocortical carcinomas. Modifications to treatment and surveillance strategies may be appropriate in this subtype.

Targeting the adenosine 2A receptor enhances chimeric antigen receptor T cell efficacy.

Chimeric antigen receptor (CAR) T cells have been highly successful in treating hematological malignancies, including acute and chronic lymphoblastic leukemia. However, treatment of solid tumors using CAR T cells has been largely unsuccessful to date, partly because of tumor-induced immunosuppressive mechanisms, including adenosine production. Previous studies have shown that adenosine generated by tumor cells potently inhibits endogenous antitumor T cell responses through activation of adenosine 2A receptors (A2ARs). Herein, we have observed that CAR activation resulted in increased A2AR expression and suppression of both murine and human CAR T cells. This was reversible using either A2AR antagonists or genetic targeting of A2AR using shRNA. In 2 syngeneic HER2+ self-antigen tumor models, we found that either genetic or pharmacological targeting of the A2AR profoundly increased CAR T cell efficacy, particularly when combined with PD-1 blockade. Mechanistically, this was associated with increased cytokine production of CD8+ CAR T cells and increased activation of both CD8+ and CD4+ CAR T cells. Given the known clinical relevance of the CD73/adenosine pathway in several solid tumor types, and the initiation of phase I trials for A2AR antagonists in oncology, this approach has high translational potential to enhance CAR T cell efficacy in several cancer types.

Merkel cell carcinoma: what makes a difference?

BACKGROUND: Merkel cell carcinoma (MCC) is a cutaneous neuroendocrine tumor that may spread via lymphatics and can therefore be staged with sentinel lymph node biopsy (SLNB). MCC is radiosensitive and chemosensitive, although the role of adjuvant therapy is still unclear. We examined the impact of different treatments on the outcome of MCC. METHODS: We performed a retrospective review of state cancer registry data from California, Oregon, and Washington of patients diagnosed with primary skin MCC between 1988 and 2012 (n = 4,038). Data were analyzed using Cox regression and Kaplan-Meier methods to examine disease-specific survival. RESULTS: Patients with positive nodes or no documented nodal evaluation had worse survival compared with node-negative patients. No nodal evaluation had decreased survival compared with lymph node evaluation by SLNB. Completion lymph node dissection conferred improved survival in patients with a positive SLNB. In clinically node-negative patients who had a positive SLNB, radiation and chemotherapy did not affect survival. CONCLUSIONS: Lymph node evaluation is an important component to MCC treatment. The role of adjuvant radiation and chemotherapy needs further evaluation.

Sentinel lymph node biopsy for melanoma: comparison of lymphocele rates by surgical technique.

Lymphocele is a common wound complication of sentinel lymph node biopsy (SLNB). The surgical technique may play a key role in lymphocele formation. This study compared rates of postoperative lymphocele formation by different surgical techniques (Harmonic Scalpel [HS], LigaSure [LS], and traditional electrocautery with clips) after SLNB in the groin or axilla for the staging of clinically node-negative cutaneous melanoma. Patients were selected by convenience sample from a single-institution, single-surgeon, prospectively collected melanoma database over a 27-month period. One hundred fifty consecutive patients underwent SLNB, 70 with clips, 37 with HS, and 43 with LS. The median number of nodes removed was two and did not vary significantly between groups. Twenty-three lymphoceles occurred for an overall rate of 15 per cent; rates were 9.9 and 26.5 per cent for the axilla and groin, respectively. Sixteen (70%) were aspirated for size or symptoms; lymphoceles after groin SLNB were significantly (P = 0.03) more likely to require aspiration. Lymphocele rates for the clip, HS, and LS groups were 20.0, 18.9, and 4.7 per cent, respectively. The differences between the LS and other groups were statistically significant. Use of the LS may lead to lower lymphocele rates after groin and axillary SLNB compared with electrocautery and clips.

Effect of biopsy type on outcomes in the treatment of primary cutaneous melanoma.

BACKGROUND: Surgical excision remains the primary and only potentially curative treatment for melanoma. Although current guidelines recommend excisional biopsy as the technique of choice for evaluating lesions suspected of being primary melanomas, other biopsy types are commonly used. We sought to determine the impact of biopsy type (excisional, shave, or punch) on outcomes in melanoma. METHODS: A prospectively collected, institutional review board-approved database of primary clinically node-negative melanomas (stages cT1-4N0) was reviewed to determine the impact of biopsy type on T-staging accuracy, wide local excision (WLE) area (cm(2)), sentinel lymph node biopsy (SLNB) identification rates and results, tumor recurrence, and patient survival. RESULTS: Seven hundred nine patients were diagnosed by punch biopsy (23%), shave biopsy (34%), and excisional biopsy (43%). Shave biopsy results showed significantly more positive deep margins (P < .001). Both shave and punch biopsy results showed more positive peripheral margins (P < .001) and a higher risk of finding residual tumor (with resulting tumor upstaging) in the WLE (P < .001), compared with excisional biopsy. Punch biopsy resulted in a larger mean WLE area compared with shave and excisional biopsies (P = .030), and this result was sustained on multivariate analysis. SLNB accuracy was 98.5% and was not affected by biopsy type. Similarly, biopsy type did not confer survival advantage or impact tumor recurrence; the finding of residual tumor in the WLE impacted survival on univariate but not multivariate analysis. CONCLUSIONS: Both shave and punch biopsies demonstrated a significant risk of finding residual tumor in the WLE, with pathologic upstaging of the WLE. Punch biopsy also led to a larger mean WLE area compared with other biopsy types. However, biopsy type did not impact SLNB accuracy or results, tumor recurrence, or disease-specific survival (DSS). Punch and shave biopsies, when used appropriately, should not be discouraged for the diagnosis of melanoma.