The Genomic, Transcriptomic, and Immunologic Landscape of HRAS Mutations in Solid Tumors.

Tipifarnib is the only targeted therapy breakthrough for HRAS-mutant (HRASmt) recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). The molecular profiles of HRASmt cancers are difficult to explore given the low frequency of HRASmt. This study aims to understand the molecular co-alterations, immune profiles, and clinical outcomes of 524 HRASmt solid tumors including urothelial carcinoma (UC), breast cancer (BC), non-small-cell lung cancer (NSCLC), melanoma, and HNSCC. HRASmt was most common in UC (3.0%), followed by HNSCC (2.82%), melanoma (1.05%), BC (0.45%), and NSCLC (0.44%). HRASmt was absent in Her2+ BC regardless of hormone receptor status. HRASmt was more frequently associated with squamous compared to non-squamous NSCLC (60% vs. 40% in HRASwt, p = 0.002). The tumor microenvironment (TME) of HRASmt demonstrated increased M1 macrophages in triple-negative BC (TNBC), HNSCC, squamous NSCLC, and UC; increased M2 macrophages in TNBC; and increased CD8+ T-cells in HNSCC (all p < 0.05). Finally, HRASmt was associated with shorter overall survival in HNSCC (HR: 1.564, CI: 1.16-2.11, p = 0.003) but not in the other cancer types examined. In conclusion, this study provides new insights into the unique molecular profiles of HRASmt tumors that may help to identify new targets and guide future clinical trial design.

Bispecific antibodies and CAR-T cells: dueling immunotherapies for large B-cell lymphomas.

Despite recent advances in frontline therapy for diffuse large B-cell lymphoma (DLBCL), at least a third of those diagnosed still will require second or further lines for relapsed or refractory (rel/ref) disease. A small minority of these can be cured with standard chemoimmunotherapy/stem-cell transplant salvage approaches. CD19-directed chimeric antigen receptor T-cell (CAR-19) therapies are increasingly altering the prognostic landscape for rel/ref patients with DLBCL and related aggressive B-cell non-Hodgkin lymphomas. Long-term follow up data show ongoing disease-free outcomes consistent with cure in 30-40% after CAR-19, including high-risk patients primary refractory to or relapsing within 1 year of frontline treatment. This has made CAR-19 a preferred option for these difficult-to-treat populations. Widespread adoption, however, remains challenged by logistical and patient-related hurdles, including a requirement for certified tertiary care centers concentrated in urban centers, production times of at least 3-4 weeks, and high per-patients costs similar to allogeneic bone-marrow transplantation. Bispecific antibodies (BsAbs) are molecular biotherapies designed to bind and activate effector T-cells and drive them to B-cell antigens, leading to a similar cellular-dependent cytotoxicity as CAR-19. May and June of 2023 saw initial approvals of next-generation BsAbs glofitamab and epcoritamab in DLBCL as third or higher-line therapy, or for patients ineligible for CAR-19. BsAbs have similar spectrum but generally reduced severity of immune related side effects as CAR-19 and can be administered in community settings without need to manufacture patient-specific cellular products. To date and in contrast to CAR-19, however, there is no convincing evidence of cure after BsAbs monotherapy, though follow up is limited. The role of BsAbs in DLBCL treatment is rapidly evolving with trials investigating use in both relapsed and frontline curative-intent combinations. The future of DLBCL treatment is bound increasingly to include effector cell mediated immunotherapies, but further optimization of both cellular and BsAb approaches is needed.

Functional drivers of resistance to anti-CD19 CAR-T cell therapy in diffuse large B cell lymphoma.

Chimeric antigen receptor T-cell therapy targeting CD19 (CAR-19) promotes impressive durable remissions for relapsed or refractory (rel/ref) large B-cell lymphoma (LBCL) patients with historically poor prognoses. Despite this, over half of patients still fail to respond or eventually progress. Studies to reveal mechanisms of resistance have examined host clinical parameters, CAR-19 product composition, and tumor microenvironment (TME) alterations, while a relative paucity of studies has analyzed contributions by genomic alterations in tumor cells. Factors associated with outcome include increased tumor volume, specific characteristics of infused CAR-T products, infiltration by myeloid cells in tumor microenvironments, and markers of complexity in LBCL genomes. Functional laboratory studies of resistance are largely absent in the current literature, illustrating a need for experiments in genetically accurate immunocompetent systems to confirm candidate alterations' roles in resistance and inform future improvements. In this review, we highlight key studies that have elucidated biomarkers of resistance in hosts, CAR products, TMEs, and comparatively understudied tumor-intrinsic mediators encoded by tumor genomes. We conclude with an experimental framework suitable for CAR-19 resistance biomarker identification and laboratory functional validation.

Efficacy of checkpoint inhibition after CAR-T failure in aggressive B-cell lymphomas: outcomes from 15 US institutions.

Checkpoint inhibitor (CPI) therapy with anti-PD-1 antibodies has been associated with mixed outcomes in small cohorts of patients with relapsed aggressive B-cell lymphomas after CAR-T failure. To define CPI therapy efficacy more definitively in this population, we retrospectively evaluated clinical outcomes in a large cohort of 96 patients with aggressive B-cell lymphomas receiving CPI therapy after CAR-T failure across 15 US academic centers. Most patients (53%) had diffuse large B-cell lymphoma, were treated with axicabtagene ciloleucel (53%), relapsed early (≤180 days) after CAR-T (83%), and received pembrolizumab (49%) or nivolumab (43%). CPI therapy was associated with an overall response rate of 19% and a complete response rate of 10%. Median duration of response was 221 days. Median progression-free survival (PFS) and overall survival (OS) were 54 and 159 days, respectively. Outcomes to CPI therapy were significantly improved in patients with primary mediastinal B-cell lymphoma. PFS (128 vs 51 days) and OS (387 vs 131 days) were significantly longer in patients with late (>180 days) vs early (≤180 days) relapse after CAR-T. Grade ≥3 adverse events occurred in 19% of patients treated with CPI. Most patients (83%) died, commonly because of progressive disease. Only 5% had durable responses to CPI therapy. In the largest cohort of patients with aggressive B-cell lymphoma treated with CPI therapy after CAR-T relapse, our results reveal poor outcomes, particularly among those relapsing early after CAR-T. In conclusion, CPI therapy is not an effective salvage strategy for most patients after CAR-T, where alternative approaches are needed to improve post-CAR-T outcomes.

A single-center analysis of patients with extranodal marginal zone lymphoma of the breast.

Breast extranodal marginal zone lymphoma (EMZL) is a rare malignancy. We performed the largest published to date single-center retrospective analysis of 13 patients with breast EMZL focusing on clinical characteristics and treatment-related outcomes. The rarity of this disease at our center was concordant with the prevalence reported in the literature, with breast EMZL comprising 2% of 654 MZL cases. Most patients presented with stage I-II disease however four (30.8%) patients had stage IV disease mostly due to occult bone marrow (BM) involvement. Interestingly, EMZL was frequently non-FDG avid (66.7%) on staging PET/CT. With a median follow-up of 3.1 years (range 5 months to 10.2 years), the 3-year progression free survival was 68.7% (95%CI 30.2%-88.9%) and overall survival 80.2% (95%CI 40.3%-94.8%). No patient experienced higher-grade transformation. Herein we show that localized breast EMZL can be effectively treated with radiation therapy providing long term disease control.

Marginal zone lymphoma of the colon: case series from a single center and SEER data review.

Colon extranodal marginal zone lymphoma (EMZL) is poorly characterized in the literature. We performed a retrospective review of patients with colon EMZL at our institution and from the Surveillance Epidemiology and End Results (SEER) database. Eight patients were identified in our institution with majority (88%) presenting with stage-I disease. Initial management included active surveillance, polypectomy followed by surveillance, and surgical resection followed by chemotherapy. One patient with concurrent prostate carcinoma received radiation to the rectum. Initial therapy led to complete remission in five out of six treated patients with four of them maintaining remission at 88 months. SEER database identified 361 patients with stage-I colon EMZL. Overall survival for this cohort was 73.9% at 10 years with no significant difference in outcomes between treatment groups. Our single institution experience and the SEER data analysis emphasize indolent nature of colon EMZL and need for non-aggressive therapeutic approaches.

Potency Meets Precision in Nano-optimized Chemotherapeutics.

Chemotherapy remains the most widely used cancer treatment modality. Nanotechnology provides exciting opportunities to improve these drugs, transforming decades-old generic treatments into precise new medicines. We illustrate the potential of recent advances in nanotechnology-enhanced therapy focusing on diffuse large B-cell lymphoma (DLBCL); the most common hematologic malignancy.

Outcomes of Burkitt lymphoma with central nervous system involvement: evidence from a large multicenter cohort study.

Central nervous system (CNS) involvement in Burkitt lymphoma (BL) poses a major therapeutic challenge, and the relative ability of contemporary regimens to treat CNS involvement remains uncertain. We described prognostic significance of CNS involvement and incidence of CNS recurrence/progression after contemporary immunochemotherapy using real-world clinicopathologic data on adults with BL diagnosed between 2009 and 2018 across 30 US institutions. We examined associations between baseline CNS involvement, patient characteristics, complete response (CR) rates, and survival. We also examined risk factors for CNS recurrence. Nineteen percent (120/641) of patients (age 18-88 years) had CNS involvement. It was independently associated with HIV infection, poor performance status, involvement of ≥2 extranodal sites, or bone marrow involvement. First-line regimen selection was unaffected by CNS involvement (P=0.93). Patients with CNS disease had significantly lower rates of CR (59% versus 77% without; P<0.001), worse 3-year progression-free survival (adjusted hazard ratio [aHR], 1.53, 95% confidence interval [CI], 1.14-2.06, P=0.004) and overall survival (aHR, 1.62, 95%CI, 1.18-2.22, P=0.003). The 3-year cumulative incidence of CNS recurrence was 6% (95%CI, 4-8%). It was significantly lower among patients receiving other regimens (CODOX-M/IVAC, 4%, or hyperCVAD/MA, 3%) compared with DA-EPOCH-R (13%; adjusted sub-HR, 4.38, 95%CI, 2.16-8.87, P<0.001). Baseline CNS involvement in BL is relatively common and portends inferior prognosis independent of first-line regimen selection. In real-world practice, regimens with highly CNS-penetrant intravenous systemic agents were associated with a lower risk of CNS recurrence. This finding may be influenced by observed suboptimal adherence to the strict CNS staging and intrathecal therapy procedures incorporated in DA-EPOCH-R.

Optimized Doxorubicin Chemotherapy for Diffuse Large B-cell Lymphoma Exploits Nanocarrier Delivery to Transferrin Receptors.

New treatments are needed to address persistent unmet clinical needs for diffuse large B-cell lymphoma (DLBCL). Overexpression of transferrin receptor 1 (TFR1) is common across cancer and permits cell-surface targeting of specific therapies in preclinical and clinical studies of various solid tumors. Here, we developed novel nanocarrier delivery of chemotherapy via TFR1-mediated endocytosis, assessing this target for the first time in DLBCL. Analysis of published datasets showed novel association of increased TFR1 expression with high-risk DLBCL cases. Carbon-nitride dots (CND) are emerging nanoparticles with excellent in vivo stability and distribution and are adaptable to covalent conjugation with multiple substrates. In vitro, linking doxorubicin (Dox) and transferrin (TF) to CND (CND-Dox-TF, CDT) was 10-100 times more potent than Dox against DLBCL cell lines. Gain- and loss-of-function studies and fluorescent confocal microscopy confirmed dependence of these effects on TFR1-mediated endocytosis. In contrast with previous therapeutics directly linking Dox and TF, cytotoxicity of CDT resulted from nuclear entry by Dox, promoting double-stranded DNA breaks and apoptosis. CDT proved safe to administer in vivo, and when incorporated into standard frontline chemoimmunotherapy in place of Dox, it improved overall survival by controlling patient-derived xenograft tumors with greatly reduced host toxicities. Nanocarrier-mediated Dox delivery to cell-surface TFR1, therefore, warrants optimization as a potential new therapeutic option in DLBCL. SIGNIFICANCE: Targeted nanoparticle delivery of doxorubicin chemotherapy via the TRF1 receptor presents a new opportunity against high-risk DLBCL tumors using potency and precision.

T Cell-Activating Bispecific Antibodies in Cancer Therapy.

Effector lymphocytes are multifunctional cells of the immune system that promote cytolysis of pathogen-infected cells and nascent tumors. Tumors must learn to evade effectors and employ a wide variety of mechanisms to do so. Bispecific Abs (BsAbs) are an emerging cancer immunotherapy approach seeking to re-engage either T effectors or NK cells with malignant cells. Possessing specificity for effector cells on one end and a tumor Ag on the other, these molecules work by attracting effectors to the target cell to build an immunologic synapse and induce tumor cell killing. The BsAb blinatumomab, for example, has specificity for the T cell-activating cell surface protein CD3 and the B cell Ag CD19. The only BsAb with regulatory approval currently, blinatumomab is used in the treatment of relapsed or refractory B cell acute lymphoblastic leukemia. Many additional BsAbs are in preclinical development, however, targeting many different tumor types. The variety of potential effector cells and cancer Ags, along with potential combination therapies, make BsAbs an active area of drug development. In this review, we discuss cancer recognition by the immune system and structural and mechanistic aspects of BsAbs. We summarize key steps in preclinical development and subsequent translation to medical practice. Future directions for BsAbs include combinations with a wide variety of both immunologic and nonimmunologic therapies. Defining their optimum clinical use is at early stages.

Interstitial nephritis in melanoma patients secondary to PD-1 checkpoint inhibitor.

BACKGROUND: Immune checkpoint inhibitors have become the first line therapy in melanoma treatment and their use is extending to other malignancies. However, we are still learning about immune side effects produced by these drugs and their severity especially in patients with history of inflammatory diseases. CASE PRESENTATION: We present two cases of metastatic melanoma treated with nivolumab and pembrolizumab (anti PD-1). Both patients developed acute interstitial nephritis during immune checkpoint therapy. We emphasize the causal association between immune checkpoint inhibitors and the nephritis. The timing of drug administration and appearance of nephritis is suggestive of a causal relation between the checkpoint inhibitor therapy and this adverse event. CONCLUSIONS: Although uncommon, some side effects from checkpoint inhibitors can be severe and may need to be addressed with immunosuppression. Given the increasing frequency of immunotherapy use, awareness should be raised in regards to immune side effects and their appropriate management.