Chimeric Antigen Receptor (CAR) T cell therapies - adoptive T cell therapies that have been genetically engineered for a new antigen-specificity - have displayed significant success in treating ...patients with hematologic malignancies, leading to three recent US Food and Drug Administration approvals. Based on the promise generated from these successes, the field is rapidly evolving to include new disease indications and CAR designs, while simultaneously reviewing and optimizing toxicity and management protocols. As such, this review provides expert perspective on the significance and clinical considerations of CAR T cell therapies in order to provide timely information to clinicians about this revolutionary new therapeutic class.
•Axicabtagene ciloleucel induced long-term survival with no new safety signals in patients with refractory LBCL.•Durable responses were associated with expansion of chimeric antigen receptor T cells ...early after intravenous infusion.
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In phase 2 of ZUMA-1, a single-arm, multicenter, registrational trial, axicabtagene ciloleucel (axi-cel) autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy demonstrated durable responses at 2 years in patients with refractory large B-cell lymphoma (LBCL). Here, we assessed outcomes in ZUMA-1 after 5 years of follow-up. Eligible adults received lymphodepleting chemotherapy followed by axi-cel (2 × 106 cells per kg). Investigator-assessed response, survival, safety, and pharmacokinetics were assessed in patients who had received treatment. The objective response rate in these 101 patients was 83% (58% complete response rate); with a median follow-up of 63.1 months, responses were ongoing in 31% of patients at data cutoff. Median overall survival (OS) was 25.8 months, and the estimated 5-year OS rate was 42.6%. Disease-specific survival (excluding deaths unrelated to disease progression) estimated at 5 years was 51.0%. No new serious adverse events or deaths related to axi-cel were observed after additional follow-up. Peripheral blood B cells were detectable in all evaluable patients at 3 years with polyclonal B-cell recovery in 91% of patients. Ongoing responses at 60 months were associated with early CAR T-cell expansion. In conclusion, this 5-year follow-up analysis of ZUMA-1 demonstrates sustained overall and disease-specific survival, with no new safety signals in patients with refractory LBCL. Protracted B-cell aplasia was not required for durable responses. These findings support the curative potential of axi-cel in a subset of patients with aggressive B-cell lymphomas. This trial was registered at ClinicalTrials.gov, as #NCT02348216.
Neelapu et al report on a 5-year follow-up of the ZUMA-1 trial of axicabtagene ciloleucel (axi-cel) autologous anti-CD19 chimeric antigen receptor T-cell therapy for refractory large B-cell lymphoma (LBCL) and confirm sustained response in those achieving complete response. At 5 years, 31% of treated patients had sustained responses, with an overall 5-year survival of 42.6%, increasing the probability that axi-cel has curative potential for a subset of patients with refractory aggressive LBCL.
The clinical challenge posed by p53 abnormalities in hematological malignancies requires therapeutic strategies other than standard genotoxic chemotherapies. ONC201 is a first-in-class small molecule ...that activates p53-independent apoptosis, has a benign safety profile, and is in early clinical trials. We found that ONC201 caused p53-independent apoptosis and cell cycle arrest in cell lines and in mantle cell lymphoma (MCL) and acute myeloid leukemia (AML) samples from patients; these included samples from patients with genetic abnormalities associated with poor prognosis or cells that had developed resistance to the nongenotoxic agents ibrutinib and bortezomib. Moreover, ONC201 caused apoptosis in stem and progenitor AML cells and abrogated the engraftment of leukemic stem cells in mice while sparing normal bone marrow cells. ONC201 caused changes in gene expression similar to those caused by the unfolded protein response (UPR) and integrated stress responses (ISRs), which increase the translation of the transcription factor ATF4 through an increase in the phosphorylation of the translation initiation factor eIF2α. However, unlike the UPR and ISR, the increase in ATF4 abundance in ONC201-treated hematopoietic cells promoted apoptosis and did not depend on increased phosphorylation of eIF2α. ONC201 also inhibited mammalian target of rapamycin complex 1 (mTORC1) signaling, likely through ATF4-mediated induction of the mTORC1 inhibitor DDIT4. Overexpression of BCL-2 protected against ONC201-induced apoptosis, and the combination of ONC201 and the BCL-2 antagonist ABT-199 synergistically increased apoptosis. Thus, our results suggest that by inducing an atypical ISR and p53-independent apoptosis, ONC201 has clinical potential in hematological malignancies.
The nuclear transporter exportin‐1 (XPO1) is highly expressed in mantle cell lymphoma (MCL) cells, and is believed to be associated with the pathogenesis of this disease. XPO1‐selective inhibitors of ...nuclear export (SINE) compounds have been shown to induce apoptosis in MCL cells. Given that p53 is a cargo protein of XPO1, we sought to determine the significance of p53 activation through XPO1 inhibition in SINE‐induced apoptosis of MCL cells. We investigated the prognostic impact of XPO1 expression in MCL cells using Oncomine analysis. The significance of p53 mutational/functional status on sensitivity to XPO1 inhibition in cell models and primary MCL samples, and the functional role of p53‐mediated apoptosis signaling, were also examined. Increased XPO1 expression was associated with poor prognosis in MCL patients. The XPO1 inhibitor KPT‐185 induced apoptosis in MCL cells through p53‐dependent and ‐independent mechanisms, and p53 status was a critical determinant of its apoptosis induction. The KPT‐185‐induced, p53‐mediated apoptosis in the MCL cells occurred in a transcription‐dependent manner. Exportin‐1 appears to influence patient survival in MCL, and the SINE XPO1 antagonist KPT‐185 effectively activates p53‐mediated transcription and apoptosis, which would provide a novel strategy for the therapy of MCL.
The selective XPO1 inhibitor KPT‐185 potently activates p53‐mediated transcription toward apoptosis in MCL. XPO1 inhibitors may provide a novel therapeutic tool for the therapy of MCL that often has suppressed p53 and high levels of XPO1.
Summary Background The combination of rituximab and lenalidomide has shown promise for the treatment of mantle-cell lymphoma (MCL) in preclinical studies. We aimed to identify the maximum tolerated ...dose (MTD) of lenalidomide when combined with rituximab in a phase 1 trial and to assess the efficacy and safety of this combination in a phase 2 trial in patients with relapsed or refractory MCL. Methods Patients with relapsed or refractory MCL who had received one to four previous lines of treatment were enrolled in this single-arm, open-label, phase 1/2 trial at MD Anderson Cancer Center. In phase 1, to identify the MTD of lenalidomide, four patient cohorts received escalating doses (10, 15, 20, and 25 mg) of daily oral lenalidomide on days 1–21 of each 28-day cycle. 375 mg/m2 intravenous rituximab was also administered in four weekly doses during cycle 1 only. In phase 2, patients received rituximab plus the MTD of lenalidomide, following the same cycles as for phase 1. Treatment in both phases continued until disease progression, stem-cell transplantation, or severe toxicity. The primary efficacy endpoint was overall response (complete or partial response). The secondary efficacy endpoint was survival. We used the Kaplan-Meier method to estimate response duration, progression-free survival, and overall survival. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov , number NCT00294632. Findings 52 patients were enrolled between Feb 10, 2006 and July 30, 2009, 14 in phase 1 and 44 (including six patients who received the MTD of lenalidomide in the phase 1 portion) in phase 2. The MTD was 20 mg lenalidomide. One patient who was treated with 25 mg lenalidomide developed a grade 4 non-neutropenic infection and died. In the phase 2 portion of the study, grade 3–4 haematological toxicities included neutropenia (29 patients), lymphopenia (16 patients), leucopenia (13 patients), and thrombocytopenia (ten patients). There were only two episodes of febrile neutropenia. Among 44 patients in phase 2, 25 (57%) had an overall response: 16 (36%) had a complete response and nine (20%) had a partial response. The median response duration was 18·9 months (95% CI 17·0 months to not reached NR). The median progression-free survival was 11·1 months (95% CI 8·3 to 24·9 months), and the median overall survival was 24·3 months (19·8 months to NR). Five of 14 patients who had received bortezomib treatment before enrolment achieved an overall response. Interpretation Oral lenalidomide plus rituximab is well tolerated and effective for patients with relapsed or refractory MCL. Funding Celgene.
The in vivo persistence of adoptively transferred T cells is predictive of antitumor response. Identifying functional properties of infused T cells that lead to in vivo persistence and tumor ...eradication has remained elusive. We profiled CD19-specific chimeric antigen receptor (CAR) T cells as the infusion products used to treat large B cell lymphomas using high-throughput single-cell technologies based on time-lapse imaging microscopy in nanowell grids (TIMING), which integrates killing, cytokine secretion, and transcriptional profiling. Our results show that the directional migration of CD19-specific CAR T cells is correlated with multifunctionality. We showed that CD2 on T cells is associated with directional migration and that the interaction between CD2 on T cells and CD58 on lymphoma cells accelerates killing and serial killing. Consistent with this, we observed that elevated CD58 expression on pretreatment tumor samples in patients with relapsed or refractory large B cell lymphomas treated with CD19-specific CAR T cell therapy was associated with complete clinical response and survival. These results highlight the importance of studying dynamic T cell-tumor cell interactions in identifying optimal antitumor responses.
Immune effector cell (IEC) therapies offer durable and sustained remissions in significant numbers of patients with hematological cancers. While these unique immunotherapies have improved outcomes ...for pediatric and adult patients in a number of disease states, as ‘living drugs,’ their toxicity profiles, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), differ markedly from conventional cancer therapeutics. At the time of article preparation, the US Food and Drug Administration (FDA) has approved tisagenlecleucel, axicabtagene ciloleucel, and brexucabtagene autoleucel, all of which are IEC therapies based on genetically modified T cells engineered to express chimeric antigen receptors (CARs), and additional products are expected to reach marketing authorization soon and to enter clinical development in due course. As IEC therapies, especially CAR T cell therapies, enter more widespread clinical use, there is a need for clear, cohesive recommendations on toxicity management, motivating the Society for Immunotherapy of Cancer (SITC) to convene an expert panel to develop a clinical practice guideline. The panel discussed the recognition and management of common toxicities in the context of IEC treatment, including baseline laboratory parameters for monitoring, timing to onset, and pharmacological interventions, ultimately forming evidence- and consensus-based recommendations to assist medical professionals in decision-making and to improve outcomes for patients.
Cancer immunotherapy has greatly advanced in recent years, with chimeric antigen receptor (CAR) T cells emerging as an innovative technology that harnesses the immune system to fight malignant ...diseases. These genetically engineered T‐cells have shown encouraging results for B‐cell lymphoid malignancies and are now being explored for other cancer types. However, this novel adoptive cell therapy is associated with a new spectrum of immune‐mediated adverse events and toxicities. As CAR T cells recognize and engage tumour cells, cytokines are secreted and activate other immune cells, frequently leading to rapid development of cytokine release syndrome, which can result in acute deterioration of the patient's clinical condition. In many patients, cytokine release syndrome is mild and easy to manage, but others experience persistent fevers accompanied by hypotension and hypoxia, which require management with immune‐modulatory agents. Another deleterious effect of cytokines released by effector cells is immune effector cell–associated neurotoxicity syndrome. This syndrome, caused by a disruption of the blood–brain barrier as a consequence of the immune process, can result in rapid deterioration in cognitive function. This is often associated with subtle changes in handwriting, often progressing to loss of memory and concentration and reduced ability to name objects or follow commands. In some cases, the neurological state is further compromised by seizures and in rare instances with fulminant life‐threatening cerebral oedema. In this review, we discuss these toxicities, as well as other CAR T‐cell–related immune phenomenon, and address their clinical manifestations, grading, and management options.
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