Assessment of Image-Guided Intratumoral Delivery of Immunotherapeutics in Patients With Cancer.

Importance: Direct intratumoral delivery of immunotherapies is a compelling approach to overcoming barriers to systemic immunotherapy efficacy. While the use of intratumoral delivery of immunotherapy drugs is increasing rapidly in both the investigational and standard of care domains, the feasibility and safety of these interventions, particularly for deeper lesions that require image-guidance, remain unknown. Objective: To address current knowledge gaps in image-guided techniques for intratumoral immunotherapy delivery and the safety of these interventions. Design, Setting, and Participants: This case series study was performed at a single tertiary cancer center over a 2-year period from January 2016 to January 2018. Patients were followed until January 2019. All patients who underwent image-guided intratumoral delivery of immunotherapy agents in the standard of care, off-label, or investigational setting during the study period were included. Data were analyzed from February 1 to June 1, 2019. Exposures: Image-guided biopsies and intratumoral injections of immunotherapies across several clinical trials as well as standard of care talimogene laherparepvec therapy. Main Outcomes and Measures: Technical success, defined as the delivery of the prescribed injectate volume in its entirety, for image-guided biopsy and injections and procedure-related adverse events. Results: A total of 85 patients (median [interquartile range] age, 61 [47-71] years; 42 [52%] men) underwent 498 encounters during the study period. These encounters comprised 327 image-guided intratumoral investigational agent injections in 67 patients in clinical trials, including 33 patients with melanoma (50%), 14 patients with sarcoma (21%), 3 patients with ovarian cancer (4.5%), 2 patients with breast cancer (3%), and 2 patients with colon cancer (3%). An additional 18 patients with melanoma underwent 113 image-guided talimogene laherparepvec injections. There were no adverse events reported related to the technical component of the procedure, specifically needle insertion or biopsy. Serious adverse events (Common Terminology Criteria for Adverse Events score ≥3), including dyspnea and severe flu-like symptoms developing within 24 hours of the injection and requiring hospitalization, occurred after 3 of 327 investigational agent injections (2%) and 4 of 113 talimogene laherparepvec injections (4%). Conclusions and Relevance: The findings of this case series study suggest that intratumoral injections of immunotherapies were feasible across a range of histological conditions and target organs. Immediate postdelivery anticipated adverse events occurred in a small number of instances. Performing physicians should have the necessary safeguards in place to respond as needed. Optimal methods for intratumoral drug delivery remain unresolved, and efforts to standardize drug delivery techniques are required.

Chimeric antigen receptor T-cell therapy - assessment and management of toxicities.

Immunotherapy using T cells genetically engineered to express a chimeric antigen receptor (CAR) is rapidly emerging as a promising new treatment for haematological and non-haematological malignancies. CAR-T-cell therapy can induce rapid and durable clinical responses, but is associated with unique acute toxicities, which can be severe or even fatal. Cytokine-release syndrome (CRS), the most commonly observed toxicity, can range in severity from low-grade constitutional symptoms to a high-grade syndrome associated with life-threatening multiorgan dysfunction; rarely, severe CRS can evolve into fulminant haemophagocytic lymphohistiocytosis (HLH). Neurotoxicity, termed CAR-T-cell-related encephalopathy syndrome (CRES), is the second most-common adverse event, and can occur concurrently with or after CRS. Intensive monitoring and prompt management of toxicities is essential to minimize the morbidity and mortality associated with this potentially curative therapeutic approach; however, algorithms for accurate and consistent grading and management of the toxicities are lacking. To address this unmet need, we formed a CAR-T-cell-therapy-associated TOXicity (CARTOX) Working Group, comprising investigators from multiple institutions and medical disciplines who have experience in treating patients with various CAR-T-cell therapy products. Herein, we describe the multidisciplinary approach adopted at our institutions, and provide recommendations for monitoring, grading, and managing the acute toxicities that can occur in patients treated with CAR-T-cell therapy.

A critical assessment of adjuvant radiotherapy for inguinal lymph node metastases from melanoma.

BACKGROUND: Although patients with inguinal or pelvic lymph node (LN) metastases from melanoma may develop regional recurrence after dissection, the role of adjuvant radiotherapy remains controversial. METHODS: The medical records of 40 patients with inguinal and/or pelvic lymph node metastases from melanoma were reviewed retrospectively. Indications for adjuvant radiotherapy included the following nodal characteristics: extracapsular extension, LNs > or =3 cm in diameter, > or =4 involved LNs, and LN recurrence after prior nodal surgery. Thirty-seven of 40 patients underwent formal LN dissection. Three patients had only local excision of gross disease for recurrence after prior dissection. All patients received radiation to a median dose of 30 Gy at six Gy/fraction delivered twice weekly. RESULTS: With a median follow-up time of 22.5 months, the 3-year actuarial distant metastasis-free and overall survival rates were 35% and 38%, respectively. The 3-year regional control rate was 74%. Univariate analyses of patient, tumor, and treatment characteristics failed to reveal any association with distant metastasis-free survival, overall survival, or regional control. Regional failures occurred in nine patients; seven of these were isolated dermal failures within the field of irradiation. Only two patients (5%) had LN basin recurrences; one of these patients also developed dermal recurrence. Fifteen of 40 patients developed lymphedema; in seven of these, lymphedema was present before initiation of radiation therapy. CONCLUSIONS: Radiation may prevent recurrence of nodal disease in patients at high risk for regional failure, but in-field dermal recurrences may sometimes occur (8 of 40, 20%). Treatment-related lymphedema and death from metastatic melanoma were common.