BACKGROUND: Patients with relapsed or refractory large B-cell lymphoma (LBCL) who have relapsed after at least 2 lines of therapy had a poor prognosis before the introduction of chimeric antigen receptor (CAR) T-cell therapy. The FDA approved three CD19 CAR T-cell products, axicabtagene ciloleucel (axi-cel), tisagenlecleucel, and lisocabtagene maraleucel (liso-cel), based on the results of pivotal phase 2 clinical trials. High response rates and long-term remissions in these multiply relapsed patients led to randomized trials as a second-line therapy against the current standard of care for primary refractory and early relapsing LBCL. Axi-cel and liso-cel are now approved as second-line treatments for patients with relapsed or refractory large B-cell lymphoma based on these trials, while tisagenlecleucel failed to improve upon second-line standard of care. This has led to greater axi-cel and liso-cel usage as compared with tisagenlecleucel. Clinical trials and real-world trials show a higher toxicity profile for axi-cel as compared to liso-cel with similar efficacy outcomes, leading to selection of liso-cel for older patients with more medical comorbidities. However, axi-cel manufacturing is faster and more reliable making it a preferred choice for rapidly progressive lymphomas. No direct comparison has been made between the two in order to optimally inform product selection. OBJECTIVE: We aimed to compare the toxicity profile and efficacy outcomes between two cohorts, one treated with axi-cel and the other with liso-cel, ideally well matched, during the same period of time. METHODS: We retroactively gathered patient data for patients treated between June 2021 to September 2022 with both products. We compared the cohorts for patient characteristics that are proven to affect the toxicity and efficacy in order to identify significant differences that could influence our results and to increase the likelihood that the two cohorts were well matched. We then assessed associated toxicities and long-term efficacy outcomes. RESULTS: The two cohorts were comparable for all patient and disease variables other than age (median age of 62 years old in axi-cel compared to 71 years old liso-cel [p < 0.001]). There was no significant difference between high-grade cytokine release syndrome (CRS) (3% vs 5% for axi-cel vs. liso-cel cohorts, respectively; p = 0.58), high-grade immune effector cell-associated neurotoxicity syndrome (ICANS) (18% [ASTCT] or 19% [CTCAE], 14% [ASTCT] or 12% [CTCAE] for axi-cel vs. liso-cel cohorts, respectively, p = 0.055). There were higher rates of any grade CRS with axi-cel, and duration of hospitalization was longer for axi-cel vs. liso-cel (10 vs. 14 days, respectively). Best overall response rates (ORR) (93% vs. 84% axi-cel vs. liso-cel, respectively) and complete response (CR) rates (71% vs. 56% axi-cel vs liso-cel, respectively) did not statistically differ between the two groups. 12-month overall survival (OS) (76% vs. 81% axi-cel vs. liso-cel, respectively) and progression free survival (PFS) (61% vs. 45% of patients axi-cel vs. liso-cel, respectively) did not statistically differ between the two groups (p =0.94, p =0.51 for OS and PFS, respectively). CONCLUSIONS: Our study showed both products are similar in their high-grade toxicity profile as well as their efficacy. While axi-cel has more any grade CRS and ICANS, the lack of significantly higher high-grade toxicities likely reflects better and more aggressive toxicity mitigation strategies when patients present with low grade side effects. As a result, axi-cel in our study was found to be less toxic than previously seen in past clinical trials as well as real-world studies. Many factors go into selection of a CAR T-cell product, ranging from product performance attributes like safety and efficacy, to product manufacturing qualities like turnaround time and fidelity of manufacturing. With equivalency with regards to product performance, manufacturing qualities may then be most important in guiding product selection for LBCL patients.

In the last decade cancer immunotherapy has taken huge strides forward from bench to bedside and being approved as drugs. Cancer immunotherapy harnesses the power of patient’s own immune system to fight cancer. Approaches are diverse and include antibodies, therapeutic vaccines, adoptively transferred T-cells, immune checkpoint inhibitors, oncolytic viruses and immune cell activators such as toll-like receptor (TLR) agonists. Excellent clinical responses have been observed for certain cancers with checkpoint antibodies and chimeric antigen receptor (CAR)-engineered T-cells. It is however becoming evident that strategies need to be combined for broader effective treatment responses because cancers evolve to escape immune recognition. A conditionally replication-competent oncolytic adenovirus (Ad5PTDf35-[Δ24]) was engineered to secrete Helicobacter pylori Neutrophil Activating Protein (HP-NAP, a TLR-2 agonist) to combine viral oncolysis and immune stimulation. Treatment with Ad5PTDf35-[Δ24-sNAP] improved survival of mice bearing human neuroendocrine tumors (BON). Expression of HP-NAP in the tumor microenvironment promoted neutrophil infiltration, proinflammatory cytokine secretion and increased necrosis. We further studied the ability of HP-NAP to activate dendritic cells (DCs) a key player in priming T-cell responses. HP-NAP phenotypically matured and activated DCs to secrete the T-helper type-1 (Th-1) polarizing cytokine IL-12. HP-NAP-matured DCs were functional; able to migrate to draining lymph nodes and prime antigen-specific T-cell proliferation. CAR T-cells were engineered to secrete HP-NAP upon T-cell activation. Secreted HP-NAP was able to mature DCs, leading to a reciprocal effect on the CAR T-cells with improved cytotoxicity in vitro. Semliki Forest virus (SFV), an oncolytic virus with natural neuro-tropism was tagged with central nervous system (CNS)-specific microRNA target sequences for miR124, miR125 and miR134 to selectively attenuate virus replication in healthy CNS cells. Systemic infection of mice with the SFV4miRT did not cause encephalitis, while it retained its ability to replicate in tumor cells and cure a big proportion of mice bearing syngeneic neuroblastoma and gliomas. Therapeutic efficacy of SFV4miRT inversely correlated with type-I antiviral interferon response (IFN-β) mounted by tumor cells. In summary, combining immunotherapeutic strategies with HP-NAP is a promising approach to combat cancers and SFV4miRT is an excellent candidate for treatment of neuroblastomas and gliomas.

Up to 60% of patients with aggressive B-cell lymphoma who receive chimeric antigen receptor (CAR) T-cell therapy experience treatment failure and subsequently have a poor prognosis. Allogeneic hematopoietic stem cell transplantation (alloHSCT) remains a potentially curative approach for patients in this situation. Induction of a deep response prior to alloHSCT is crucial for long-term outcomes, but the optimal bridging strategy following relapse after CAR T-cell therapy has not yet been established. Polatuzumab vedotin, an antibody drug conjugate targeting CD79b, is a novel treatment option for use in combination with rituximab and bendamustine (Pola-BR) in relapsed or refractory disease. Patients: We report two heavily pretreated patients with primary refractory diffuse large Bcell lymphoma (DLBCL) and primary mediastinal B-cell lymphoma (PMBCL) respectively who relapsed after therapy with CAR T-cells with both nodal and extranodal manifestations of the disease. After application of three courses of Pola-BR both patients achieved a complete metabolic remission. Both patients underwent alloHSCT from a human leukocyte antigen (HLA)-mismatched donor following conditioning with busulfan and fludarabine and are disease free 362 days and 195 days after alloHSCT respectively. We conclude that Pola-BR can be an effective bridging therapy before alloHSCT of patients relapsing after CAR T-cell therapy. Further studies will be necessary to define the depth and durability of remission of this salvage regimen before alloHSCT.

Glioblastoma is the most commonly diagnosed central nervous system primary malignancy and it is considered a terminal diagnosis with few treatment options available. Glioblastoma tumors frequently develop treatment resistance due in part to their highly heterogenic nature. The heterogeneity of glioblastoma is partially attributed to the presence of glioma stem-like cells (GSC), which are highly invasive and resistant to chemotherapy and irradiation treatments. Signaling of the receptor tyrosine kinase MET is a known regulator of GSC. Glioblastoma patients have an increasingly poor prognosis that corresponds with increasing MET expression. Both GSC and MET are known to contribute to treatment resistance in glioblastoma and several MET alterations have been observed in glioblastoma. In these studies, we investigated MET alterations that are commonly found in glioblastoma. Using patient-derived xenograft (PDX) lines, the MET alterations were characterized and confirmed to be MET positive, MET amplified, or harbor a PTPRZ1-MET fusion. We also included a MET null glioblastoma PDX line. The PDX lines demonstrated markers for GSC potential with all showing neurosphere formation, the ability to initiate tumor growth in immune-compromised mice, and expression of GSC markers GFAP, Sox2, and nestin. The MET alterations were further examined by examining tyrosine kinase inhibitors' effect on viability and MET signaling. Oncogene addiction through MET amplification was found to have the best response to inhibition. The MET fusion bearing line demonstrated less sensitivity to inhibition than has been shown in other studies, indicating a need for further research into co-mutations that increase sensitivity to MET inhibition. We also investigated the efficacy of novel MET-targeting chimeric antigen receptor T cells (MET.CART cells). The MET.CART cells were able to specifically target and successfully kill MET-expressing glioblastoma cells. Together these results imply the need for more personalized treatment of glioblastoma based on the molecular biology of the tumor.