Novel chimeric antigen receptor targets and constructs for acute lymphoblastic leukemia: Moving beyond CD19.

Acute lymphoblastic leukemia (ALL) is the second most common acute leukemia in adults with a poor prognosis with relapsed or refractory (R/R) B-cell lineage ALL (B-ALL). Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has shown excellent response rates in RR B-ALL, but most patients relapse due to poor persistence of CAR T-cell therapy or other tumor-associated escape mechanisms. In addition, anti-CD19 CAR T-cell therapy causes several serious side effects such as cytokine release syndrome and neurotoxicity. In this review, we will discuss novel CAR targets, CAR constructs, and various strategies to boost CARs for the treatment of RR B-ALL. In addition, we discuss a few novel strategies developed to reduce the side effects of CAR.

Venetoclax-based therapy in treatment-naïve and relapsed/refractory acute myeloid leukemia.

Combining venetoclax with the hypomethylating agents azacitidine or decitabine has shown high complete response rates (60-70 %) in newly diagnosed (ND) acute myeloid leukemia (AML). However, studies addressing the efficacy of this approach in relapsed/refractory (R/R) AML remain limited. We conducted a retrospective analysis on patients treated with venetoclax-based therapy at a single institution. Objective response rates (ORR) and overall survival (OS) were assessed using logistic regression and Cox regression models, respectively. The total study population exhibited an ORR of 64 % with a complete remission at 34 %, complete remission with incomplete count recovery at 19%, and morphologic leukemia free state at 11 %. Patients with ND AML had a better ORR (71 %) compared to R/R AML (55 %), but the difference was not statistically significant. Median OS for the overall population was 14.4 months (range: 2-26 months). In the ND group, patients had a longer 6-month OS (82 % vs. 55 % in R/R AML), while both cohorts showed similar 12- and 24-month OS. Factors such as the hypomethylating agent chosen, adverse cytogenetics, TP53 mutations, prior hypomethylating agent use, and stem cell transplant status did not significantly affect ORR or OS. These findings support the effectiveness of venetoclax-based treatments in ND and R/R AML.

Radiomic biomarkers from chest computed tomography are assistive in immunotherapy response prediction for non-small cell lung cancer.

Background: Immunotherapies, such as programmed death 1/programmed death ligand 1 (PD-1/PD-L1) antibodies have been shown to improve overall and progression-free survival (PFS) in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). However, not all patients derive a meaningful clinical benefit. Additionally, patients receiving anti-PD-1/PD-L1 therapy can experience immune-related adverse events (irAEs). Clinically significant irAEs may require temporary pause or discontinuation of treatment. Having a tool to identify patients who may not benefit and/or are at risk for developing severe irAEs from immunotherapy will aid in an informed decision-making process for the patients and their physicians. Methods: Computed tomography (CT) scans and clinical data were retrospectively collected for this study to develop three prediction models using (I) radiomic features, (II) clinical features, and (III) radiomic and clinical features combined. Each subject had 6 clinical features and 849 radiomic features extracted. Selected features were run through an artificial neural network (NN) trained on 70% of the cohort, maintaining the case and control ratio. The NN was assessed by calculating the area-under-the-receiver-operating-characteristic curve (AUC-ROC), area-under-the-precision-recall curve (AUC-PR), sensitivity, and specificity. Results: A cohort of 132 subjects, of which 43 (33%) had a PFS ≤90 days and 89 (67%) of which had a PFS >90 days was used to develop the prediction models. The radiomic model was able to predict progression-free survival with a training AUC-ROC of 87% and testing AUC-ROC, sensitivity, and specificity of 83%, 75%, and 81%, respectively. In this cohort, the clinical and radiomic combined features did add a slight increase in the specificity (85%) but with a decrease in sensitivity (75%) and AUC-ROC (81%). Conclusions: Whole lung segmentation and feature extraction can identify those that would see a benefit from anti-PD-1/PD-L1 therapy.

PROMISE: a real-world clinical-genomic database to address knowledge gaps in prostate cancer.

PURPOSE: Prostate cancer is a heterogeneous disease with variable clinical outcomes. Despite numerous recent approvals of novel therapies, castration-resistant prostate cancer remains lethal. A "real-world" clinical-genomic database is urgently needed to enhance our characterization of advanced prostate cancer and further enable precision oncology. METHODS: The Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort (PROMISE) is a consortium whose aims are to establish a repository of de-identified clinical and genomic patient data that are linked to patient outcomes. The consortium structure includes a (1) bio-informatics committee to standardize genomic data and provide quality control, (2) biostatistics committee to independently perform statistical analyses, (3) executive committee to review and select proposals of relevant questions for the consortium to address, (4) diversity/inclusion committee to address important clinical questions pertaining to racial disparities, and (5) patient advocacy committee to understand patient perspectives to improve patients' quality of care. RESULTS: The PROMISE consortium was formed by 16 academic institutions in early 2020 and a secure RedCap database was created. The first patient record was entered into the database in April 2020 and over 1000 records have been entered as of early 2021. Data entry is proceeding as planned with the goal to have over 2500 patient records by the end of 2021. CONCLUSIONS: The PROMISE consortium provides a powerful clinical-genomic platform to interrogate and address data gaps that have arisen with increased genomic testing in the clinical management of prostate cancer. The dataset incorporates data from patient populations that are often underrepresented in clinical trials, generates new hypotheses to direct further research, and addresses important clinical questions that are otherwise difficult to investigate in prospective studies.

PI3Kinase Inhibition in Hormone Receptor-Positive Breast Cancer.

Derangement of the phosphatidylinositol-3 kinase (PI3K) pathway is implicated in several subtypes of breast cancers. Mutation or upregulation of PI3K enhances cancer cells' survival, proliferation, and ability to metastasize, making it an attractive molecular target for systemic therapy. PI3K has four isoforms, and several drugs targeting individual isoforms or pan-PI3K have been or are currently being investigated in clinical trials. However, the search for an effective PI3K inhibitor with a robust therapeutic effect and reasonable safety profile for breast cancer treatment remains elusive. This review focuses on the recently completed and ongoing clinical trials involving PI3K inhibitors as mono- or combination therapy in breast cancer. We review the salient findings of clinical trials, the therapeutic efficacy of PI3K inhibitors, and reported adverse effects leading to treatment discontinuation. Lastly, we discuss the challenges and potential opportunities associated with adopting PI3K inhibitors in the clinic.

Comprehensive review of chromophobe renal cell carcinoma.

Chromophobe renal cell carcinoma (chRCC) is the third most common type of RCC with distinct biology compared to other kidney cancer subtypes. The heterogeneity between the RCC subtypes is associated with noticeable differences in tumor aggressiveness and risk for the development of metastatic disease. ChRCC is characterized by chromosomal aneuploidy, TP53, PTEN, and mitochondrial gene mutations. Though the therapeutic landscape of clear cell RCC (ccRCC) has significantly evolved over the past decade, limited progress has been seen in chRCC due to its infrequent incidence. In fact, the therapeutic approach for chRCC is often extrapolated from ccRCC treatments or studies that combine several forms of nccRCC subtypes. In the new era of genetic profiling of tumors and targeted therapeutics, this review describes the epidemiology, pathology, molecular characteristics, and current management with ongoing clinical trials for chRCC.

Acute Myeloid Sarcoma: An Unusual Cause of Diarrhea.

A 62-year-old man with a past medical history of hypothyroidism was admitted for diarrhea and abdominal pain for three weeks. Initial workup for diarrhea was negative. His condition deteriorated after hospitalization. He underwent sigmoidoscopy which showed rectosigmoid mucosal ulceration. Pathology showed leukemic cells infiltration of the mucosa. The patient underwent bone marrow biopsy which confirmed the diagnosis of acute myeloid leukemia (AML). He received induction chemotherapy and his symptoms improved.