Background: BCMAxCD3 bispecific antibodies (BsAb) have changed the treatment landscape in relapsed refractory multiple myeloma (RRMM). However, despite high response rates, the majority of patients ...continue to relapse. Infectious complications, mainly viral, represent another challenge with BsAb, seen in up to 90% of patients with half of them requiring hospitalization. Both issues, loss of response as well as infectious complications, can be linked to impaired T-cell function potentially emerging during BsAb therapy. Most BsAbs have been developed as weekly treatments and one hypothesis is that dose dense treatment could overstimulate T cells finally leading to exhaustion and dysfunctionality. Thus, we compared T cell profiles and their functionality from patients with weekly dosing to patients who switched to a monthly schedule due to toxicity or patient request. Methods: We longitudinally biobanked peripheral blood samples of 19 patients of whom 7 switched from a weekly (q1w) to a monthly (q4w) BsAb treatment schedule. Peripheral blood mononuclear cells (PBMCs) were analysed using 16-color flow cytometry, including T-cell subset phenotyping and the exhaustion marker PD1, TIM3, SLAMF6 and KLRG1. Furthermore, CITEseq, scTCRseq, and Seahorse metabolic studies were performed on selected patients. Results: The enrolled patients were heavily pretreated with a median number of 6 prior therapy lines. All patients responded to BCMA BsAb with VGPR or better and were on treatment for >3 month. Only one patient from the q4w cohort relapsed during the study period. High-risk cytogenetics, lines of previous therapy, and penta-refractory disease status were equally distributed between patients on weekly and monthly schedule. Infectious complications occurred in 10/19 (q1w) (52.6%) and 1/7 patients (q4w) (14.2%). First, we addressed the question if a monthly treatment schedule confers less T-cell exhaustion by comparing PD-1 checkpoint expression and T-cell subsets between q1w and q4w administration. Indeed, flow cytometry showed a significant decrease in the CD4+PD1+ (36.9 vs. 21.1% p<0.05, unpaired t-test) and in the CD8+PD1+ (29.44 vs. 16.54% p<0.05) T cells. We also observed a decrease in the frequency of the effector memory subsets (CD45RA-, CD62L-, TEM) of CD4+ (66.19 vs. 49.63% p<0.05) and CD8+ (53.7 vs. 40.32% p=0.09), further supporting a concept in which a treatment free interval leads to recovery of the T-cell system. We also had access to paired samples of five patients who switched from q1w (1 st sample) to q4w dosing (2 nd sample). Here, flow cytometry showed a decrease of exhausted CD4+PD1+ T cells (33.68 vs. 21.76% p=0.046, paired t-test) and CD8+PD1+ T cells (29.2% vs. 15.1% p=0.117), confirming our cross-sectional analysis. Likewise, expression of SLAMF6, a regulator of T cell exhaustion, also decreased from weekly to monthly schedule (SLAMF6/CD4+:20.7 vs. 15.2% p=0.06; and CD8+:17.8 vs. 11.3% p=0.1), but differences were not statistically significant probably due to sample size. Our analysis on T-cell metabolism did not reveal significant differences between weekly and monthly dosing schedules. After strict quality control, three of the paired samples were further analysed using CITE-seq and scTCRseq. In line with our flow results, patients showed a significant decrease in CD8+ pre-exhausted T-cell subset (CD8+TCF-1+CD27+) (3.55 vs. 1.54% p=0.02) and CD8+ terminal differentiated effector memory T-cells (CD8+ TEMRA) (4.66 vs. 3.57% p=0.04) from weekly to monthly schedules, again suggesting recovery of the T-cells after a longer treatment-free interval. We also observed a trend towards decrease in the CD4+ effector memory subset (CD4+TEM, 6.96 vs. 4.89% p=0.07). Interestingly, the number of hyper-expanded T cell clonotypes increased from weekly to monthly dosing in paired samples. This was somewhat unexpected but expansion could be interpreted as reactivation of a few previously exhausted T cells. Conclusions: The optimal dosing schedule of bispecific antibodies has yet to be determined. Our results support a more extended dose schedule to allow T-cell-recovery between BsAb administrations. Whether such a strategy will result in higher antitumor efficacy or reduced susceptibility to infections, has to be evaluated in future studies.
Pseudo-progression and flare-up phenomena constitute a novel diagnostic challenge in the follow-up of patients treated with immune-oncology drugs. We present a case study on pulmonary flare-up after ...Idecabtagen Vicleucel (Ide-cel), a BCMA targeting CAR T-cell therapy, and used single-cell RNA-seq (scRNA-seq) to identify a Th17.1 driven autoimmune mechanism as the biological underpinning of this phenomenon. By integrating datasets of various lung pathological conditions, we revealed transcriptomic similarities between post CAR T pulmonary lesions and sarcoidosis. Furthermore, we explored a noninvasive PET based diagnostic approach and showed that tracers binding to CXCR4 complement FDG PET imaging in this setting, allowing discrimination between immune-mediated changes and true relapse after CAR T-cell treatment. In conclusion, our study highlights a Th17.1 driven autoimmune phenomenon after CAR T, which may be misinterpreted as disease relapse, and that imaging with multiple PET tracers and scRNA-seq could help in this diagnostic dilemma.
Blinatumomab, a bi‐specific T‐cell engaging CD3‐CD19 antibody construct, has shown significant activity in patients with relapsed/refractory (R/R) B‐cell acute lymphoblastic leukemia (ALL). Despite ...this improvement, most patients relapse. Here, we describe the outcome of 68 patients with R/R ALL after failure of blinatumomab therapy: 38 (56%) blinatumomab refractory; 30 (44%) relapsing after initial response. After a median follow‐up of 49 months, 9 (13%) patients remained alive. The median overall survival after blinatumomab failure was 5.2 months. At the time of failure, among 61 patients evaluated for immunophenotype, 56 (92%) had CD19‐positive blasts; only five (8%) had ALL recurrence with CD19‐negative disease. Two patients progressed with lower CD19 expression. In summary, the outcome of patients with R/R ALL after blinatumomab failure is poor and treatment of these patients remains an unmet medical need. Our findings indicate that blinatumomab therapy would not exclude a significant number of patients from the potential benefit of subsequent CD19‐directed therapies such as chimeric antigen receptor T‐cell therapy.
Biomarkers for cytopenias following CAR T-cell treatment in relapsed/refractory (RR) multiple myeloma (MM) are not completely defined. We prospectively analysed 275 sequential peripheral blood (PB) ...samples from 58 RRMM patients treated with BCMA-targeted CAR T cells, and then divided them into three groups: (i) baseline (before leukapheresis), (ii) ≤day+30, and (iii) >day+30 after CAR T-cell therapy. We evaluated laboratory data and performed flow cytometry to determine the (CAR) T-cell subsets. Baseline hyperferritinaemia was a risk factor for long-lasting grade ≥3 anaemia (r = 0.47, p < 0.001) and thrombocytopenia (r = 0.44, p = 0.002) after CAR T-cell therapy. Low baseline haemoglobin (Hb) and PLT were associated with long-lasting grade ≥3 anaemia (r = -0.56, p < 0.001) and thrombocytopenia (r = -0.44, p = 0.002) respectively. We observed dynamics of CAR-negative T-cell subsets following CAR T-cell infusion. In the late phase after CAR T-cell therapy (>day+30), CD4Tn frequency correlated with anaemia (r = 0.41, p = 0.0014) and lymphocytopenia was related to frequencies of CD8
T cells (r = 0.72, p < 0.001) and CD8Teff (r = 0.64, p < 0.001). CD4Tcm frequency was correlated with leucocytopenia (r = -0.49, p < 0.001). In summary, preexisting cytopenias and hyperferritinaemia indicated long duration of grade ≥3 post-CAR T-cell cytopenias. Prolonged cytopenia may be related to immune remodelling with a shift in the CAR-negative T-cell subsets following CAR T-cell therapy.
Odronextamab is a hinge-stabilised, fully human IgG4-based CD20 × CD3 bispecific antibody that binds CD3 on T cells and CD20 on B cells. We aimed to evaluate the safety and antitumour activity of ...odronextamab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma.
This single-arm, multicentre, phase 1, dose-escalation and dose-expansion (ELM-1) trial was conducted at ten academic sites across the USA and Germany. Patients aged 18 years or older with CD20-positive relapsed or refractory B-cell malignancies who previously received CD20-directed antibody therapy and who had at least one measurable lesion, and an ECOG performance status of 0 or 1 were included. Patients received intravenous odronextamab, according to a step-up dosing schedule in cycle 1, followed by treatment once per week at target doses ranging from 0·1 mg to 320 mg during cycles 2-4 (each cycle was 21 days). After cycle 4, maintenance treatment occurred every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint of safety was assessed by the incidence of adverse events and dose-limiting toxicities to determine the maximum tolerated dose or phase 2 dose of odronextamab, or both. Preliminary antitumour activity, as measured by objective response rate, was a secondary endpoint. This study is registered with ClinicalTrials.gov, NCT02290951.
From Feb 4, 2015, to Sept 25, 2021, 145 heavily pretreated patients (median of 3 (IQR 2-5 previous therapies) were enrolled (94 to the dose-escalation and 51 to the dose-expansion part of the study). The median age of patients was 67·0 years (IQR 57·0-73·0); 101 (70%) were male and 44 (30%) were female; most participants were White (119 82%) and not Hispanic or Latino (132 91%). 42 (29%) patients received previous CAR T therapy and 119 (82%) were refractory to the last line of therapy. Median duration of follow-up was 4·2 months (IQR 1·5-11·5). During dose escalation, odronextamab was administered up to the maximum dose of 320 mg once per week and no dose-limiting toxicities were observed. The recommended dose for expansion in patients with follicular lymphoma grade 1-3a was 80 mg and was 160 mg for patients with diffuse large B-cell lymphoma. Cytokine release syndrome and neurological treatment-emergent adverse events were predominantly low grade and did not result in treatment discontinuation. The most common grade 3 or worse treatment-emergent adverse events were anaemia (36 25%), lymphopenia (28 19%), hypophosphataemia (27 19%), neutropenia (27 19%), and thrombocytopenia (20 14%). Serious treatment-emergent adverse events occurred in 89 (61%) of 145 patients; the most frequent were cytokine release syndrome (41 28%), pyrexia (11 8%), pneumonia (nine 6%), and infusion-related reaction (six 4%). Four deaths were considered related to treatment (gastric perforation in a patient with gastric involvement by lymphoma, lung infection, pneumonia, and tumour-lysis syndrome). Objective response rate was 51% (95% CI 42-59; 72 of 142). In patients with follicular lymphoma who received odronextamab doses of 5 mg or higher, the objective response rate was 91% (95% CI 75-98; 29 of 32) and the complete response rate was 72% (95% CI 53-86; 23 of 32). In patients with diffuse large B-cell lymphoma without previous CAR T-cell therapy who received doses of 80 mg or higher, the objective response rate was 53% (eight of 15) and all responses were complete responses. In patients with diffuse large B-cell lymphoma who had previous CAR T-cell therapy and received doses of 80 mg or higher, the objective response rate was 33% (ten of 30) and complete response rate was 27% (eight of 30).
Odronextamab monotherapy showed a manageable safety profile and encouraging preliminary activity, including durable responses in heavily pretreated patients with B-cell non-Hodgkin lymphoma, supporting further clinical investigation in phase 2 and 3 trials.
Regeneron Pharmaceuticals.
e19522
Background: The Phase II L-MIND study led to accelerated US approval and EU conditional authorization of the CD19-targeted immunotherapy, tafasitamab, + lenalidomide (LEN) followed by ...tafasitamab monotherapy for patients (pts) with R/R DLBCL ineligible for autologous stem cell transplant (ASCT). Long-term L-MIND data further support the regimen. Here we present exploratory analyses of final 5-year (yr) efficacy in subgroups of interest. Methods: Pts (≥18 years) with ASCT-ineligible R/R DLBCL, 1–3 prior systemic therapies (incl. ≥1 targeting CD20) and ECOG PS 0–2 received tafasitamab for ≤12 28-day cycles (+ LEN), then alone until disease progression. Primary endpoint was objective response rate (ORR). Secondary endpoints included duration of response (DoR), progression-free survival (PFS) and overall survival (OS). Exploratory subgroup analyses including by International Prognostic Index (IPI) and time to progression after 1L (in pts with only 1 prior line) used Kaplan-Meier estimates of 5-yr endpoints. Results: As of 14 Nov, 2022 in the full analysis set (FAS; n=80), ORR was 56.2% 95% CI: 44.7–67.3. Median treatment duration was 9.0 months (mo) 0.5–73.6 and median follow-up (mFU) for OS was 65.6 mo 59.9–70.3). Median DoR was not reached (mFU: 43.7 mo 29.9–58.4). Of 18 patients in follow-up for ≥5 years, 9 received tafasitamab until end of study per protocol, 9 discontinued while in remission. RR and 5-yr rates for DoR, PFS and OS showed long-term clinical activity in all pt subgroups (Table). Conclusions: In this 5-yr subgroup analysis, a long-term clinical benefit with tafasitamab + LEN followed by tafasitamab monotherapy was observed in all subgroups of clinical interest, including pts with poor prognosis risk factors. These data suggest this immunotherapy may have curative potential, which is being explored in further studies. Clinical trial information: NCT02399085 . Table: see text
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