NK Cell Therapeutics for Hematologic Malignancies: from Potential to Fruition.

PURPOSE OF REVIEW: The current review focuses on the preclinical development and clinical advances of natural killer (NK) cell therapeutics for hematologic malignancies and offers perspective on the unmet challenges that will direct future discovery in the field. RECENT FINDINGS: Approaches to improve or re-direct NK cell anti-tumor functions against hematologic malignancies have included transgenic expression of chimeric antigen receptors (CARs), administration of NK cell engagers including BiKEs and TriKEs that enhance antibody-dependent cellular cytotoxicity (ADCC) by co-engaging NK cell CD16 and antigens on tumors, incorporation of a non-cleavable CD16 that results in enhanced ADCC, use of induced memory-like NK cells alone or in combination with CARs, and blockade of NK immune checkpoints to enhance NK cytotoxicity. Recently reported and ongoing clinical trials support the feasibility and safety of these approaches. NK cell-based therapeutic strategies hold great promise as cost-effective, off-the-shelf cell therapies for patients with relapsed and refractory hematologic diseases.

Soft Tissue and Visceral Organ Sarcomas With BCOR Alterations.

Sarcomas with BCOR alteration are a heterogenous group characterized by changes including internal tandem duplications (ITDs) and recurring fusions with CCNB3, ZC3H7B, and other rare partners. With widespread genomic testing, these alterations are now associated with histologies such as Ewing-like sarcoma (BCOR::CCNB3), high-grade endometrial stromal sarcoma (ZC3H7B::BCOR), and clear cell sarcoma of kidney (BCOR-ITD). BCOR altered sarcomas of soft tissues and organs were identified through PubMed using keywords "Sarcoma (AND) BCOR" from 2005 through October 2021. Summary statistics and outcome data were calculated using STATA v12.1. Forty-one publications described 190 patients with BCOR altered soft tissue or organ sarcomas. BCOR-ITD was most common, followed by BCOR::CCNB3, ZC3H7B::BCOR. BCOR-ITD tumors occurred mainly in infants, BCOR::CCNB3 commonly occurred in adolescent young adults, and ZC3H7B::BCOR only in adults. The most common site for BCOR::CCNB3 fused tumors was extremity, BCOR-ITD kidney and ZC3H7B::BCOR uterus. Metastasis was rare in patients with BCOR::CCNB3. While most underwent resection and chemotherapy, few received radiation. Median follow-up of survivors was 24 months. Five year overall survival for patients with BCOR::CCNB3 fusions was 68% (95% confidence interval [CI]: 46%-83%). Patients with BCOR-ITD and ZC3H7B::BCOR had worse prognoses with 5 years overall survival of 35% (95% CI: 15%-56%) and 41% (95% CI: 11%-71%), respectively, demonstrating need for collaborative efforts identifying optimal treatments to improve outcomes.

Is Detection of Relapse by Surveillance Imaging Associated With Longer Survival in Patients With Rhabdomyosarcoma?

BACKGROUND: We investigated whether surveillance imaging had an impact on post-relapse survival in patients with rhabdomyosarcoma (RMS). We hypothesized that relapse detected by imaging (group IM) would be associated with longer survival compared with relapse detected with a clinical sign or symptom (group SS). MATERIALS AND METHODS: We performed an observational multi-institutional study in 127 patients with relapsed RMS comparing overall survival (OS) after relapse using Kaplan-Meier and Cox proportional hazards analyses. RESULTS: Relapse was detected in 60 (47%) group IM and 67 (53%) SS patients. Median follow-up in survivors was 4 years (range 1.0 to 16.7 y). Four-year OS rates were similar between group IM (28%, 95% confidence interval [CI]: 14%-40%) and SS (21%, 95% CI: 11%-31%) ( P =0.14). In multivariable analyses accounting for institution, age at diagnosis, time to relapse, risk group at diagnosis, and primary site, not receiving chemotherapy (hazard ratio [HR]: 6.8, 95% CI: 2.8-16.6), radiation (HR: 3, 95% CI: 1.7-5.3), or surgery (HR: 2.8, 95% CI: 1.6-4.8) after relapse were independently associated with poor OS. CONCLUSION: These results on whether surveillance imaging provides survival benefit in patients with relapsed RMS are inconclusive. Larger studies are needed to justify current surveillance recommendations. Chemotherapy, radiotherapy and surgery to treat recurrence prolong OS.

Incidence and risk factors for secondary malignancy in patients with neuroblastoma after treatment with (131)I-metaiodobenzylguanidine.

Several reports of second malignant neoplasm (SMN) in patients with relapsed neuroblastoma after treatment with (131)I-MIBG suggest the possibility of increased risk. Incidence of and risk factors for SMN after (131)I-MIBG have not been defined. This is a multi-institutional retrospective review of patients with neuroblastoma treated with (131)I-MIBG therapy. A competing risk approach was used to calculate the cumulative incidence of SMN from time of first exposure to (131)I-MIBG. A competing risk regression was used to identify potential risk factors for SMN. The analytical cohort included 644 patients treated with (131)I-MIBG. The cumulative incidence of SMN was 7.6% (95% confidence interval [CI], 4.4-13.0%) and 14.3% (95% CI, 8.3-23.9%) at 5 and 10 years from first (131)I-MIBG, respectively. No increase in SMN risk was found with increased number of (131)I-MIBG treatments or higher cumulative activity per kilogram of (131)I-MIBG received (p = 0.72 and p = 0.84, respectively). Thirteen of the 19 reported SMN were haematologic. In a multivariate analysis controlling for variables with p < 0.1 (stage, age at first (131)I-MIBG, bone disease, disease status at time of first (131)I-MIBG), patients with relapsed/progressive disease had significantly lower risk of SMN (subdistribution hazard ratio 0.3, 95% CI, 0.1-0.8, p = 0.023) compared to patients with persistent/refractory neuroblastoma. The cumulative risk of SMN after (131)I-MIBG therapy for patients with relapsed or refractory neuroblastoma is similar to the greatest published incidence for high-risk neuroblastoma after myeloablative therapy, with no dose-dependent increase. As the number of patients treated and length of follow-up time increase, it will be important to reassess this risk.