Brittany Lovely

Nivolumab (Opdivo) monotherapy is an effective treatment approach for patients with previously treated malignant mesothelioma, according to findings from the phase 3 CONFIRM trial. 

Results showed that the trial met both its coprimary end points of overall survival (OS) and progression-free survival (PFS), expanding the treatment armamentarium for patients with relapsed/recurrent disease, according to Dean Fennell, MD, who presented the findings at the International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer.

In total, 332 adult patients with previously treated, unresectable, histologically confirmed metastatic mesothelioma were randomized to either nivolumab (n = 221) or placebo (n = 111). The median OS was 9.2 months (95% CI, 7.5-10.8) with nivolumab compared with 6.6 months (95% CI, 5.0-7.5) with placebo (HR, 0.72; 95% CI, 0.55-0.94; 

 = .02). Investigator-assessed PFS was 3.0 months with nivolumab versus 1.8 months with placebo (HR, 0.61; 95% CI, 0.48-0.77; 

“[Effective therapy] for relapsed mesothelioma is an unmet need and there have been no randomized phase 3 trials that have demonstrated overall survival [benefit] in the relapsed setting,” said Fennell, a professor and chair of thoracic medical oncology at the Leicester Cancer Research Centre at the University of Leicester in the United Kingdom. “Nivolumab is deemed a safe and effective treatment and should be considered the new treatment option for patients with relapsed mesothelioma.”

Patients with mesothelioma who had received at least 1 prior line of therapy and had an ECOG performance status of 0 or 1 were eligible to enroll in the CONFIRM trial (NCT03063450). The target sample size was 336 patients; however, enrollment was halted at 332 patients because of the coronavirus disease 2019 pandemic. Fennell noted that sufficient event and follow-up was feasible with the recruited participants. Patients were randomized 2:1 to receive 240 mg in 30-minute intravenous infusions of either nivolumab or placebo on day 1 of a 14-day cycle. The secondary outcomes were RECIST-determined PFS, response rate, and safety.

Patients were heavily pretreated with 124 patients (56%) in the nivolumab arm and 66 patients (59%) in the placebo arm having received 2 prior lines of therapy.

Further primary end point data showed that the 12-month OS rates were 39.5% (95% CI, 32.5%-46.3%) with nivolumab versus 26.9% (95% CI, 18.2%-36.4%) with placebo. The 12-month PFS rates were 14.5% (95% CI, 10.2%-19.7%) and 4.9% (1.8%-10.6%), respectively. Fennel noted that the OS data were immature, with only 232 events having occurred by the analysis out of the target of 291 events. PFS data were mature with 310 events over the target 284.

“The large majority of immunotherapy studies in relapsed mesothelioma were small phase 1b and 2 studies and the only phase 3 study (PROMISE-meso; NCT02991482) in relapsed mesothelioma unfortunately showed no difference in PFS and OS when comparing pembrolizumab (Keytruda) with single-agent chemotherapy,” Rina Hui, MBBS, PhD, said in a discussion of the CONFIRM data.

Patients were stratified by PD-L1 status; however, there was no statistically significant evidence to support the utility of PD-L1 tumor proportion score (TPS) as a predictive marker for patient selection. Fifty-six patients who received nivolumab and 24 who received placebo were classified as PD-L1 positive (TPS ≥1%), and 94 patients who received nivolumab were PD-L1 negative (TPS <1%) compared with 60 who received placebo.

The median OS for patients with PD-L1–positive disease was 8.0 months with nivolumab versus 8.7 months with placebo (HR, 0.95; 95% CI, 0.51-1.76; 

 = .864). For patients with PD-L1–negative disease, the median OS was 9.0 months versus 6.4 months, respectively (HR, 0.74; 95% CI, 0.51-1.08; 

In terms of safety, the outcomes were balanced between the 2 arms. Grade 3/4 adverse events (AEs) were reported in 45% of patients treated with nivolumab compared with 42% of patients who received placebo. Serious AEs were reported in 36% and 39%, respectively. Further, 5 (3.6%) deaths were reported in relation to a serious AE in the nivolumab arm versus 4 (5.3%) in the placebo arm.

Outcomes in CONFIRM Stratified by Histology

Participants in the CONFIRM trial were also stratified by epithelioid versus nonepithelioid histology.2 Eighty-eight percent of patients in each arm were identified as having epithelioid disease at baseline.

The median OS for epithelioid patients in the nivolumab arm (n = 195) was 9.4 months compared with 6.6 months for patients in the placebo arm (n = 98; HR, 0.71; 95% CI, 0.53-0.95; 

 = .021). The 12-month OS rates were 40.0% (95% CI, 32.6%-47.3%) and 26.7% (95% CI, 17.5%-36.8%), respectively.

For those with nonepithelioid disease, the median OS for patients in the nivolumab arm (n = 26) was 5.9 months compared with 6.7 months for patients in the placebo arm (n = 13; HR, 0.79; 95% CI, 0.35-1.79; 

 = .572). The 12-month OS rates were 34.6% (95% CI, 15.8%-54.3%) and 30.8% (95% CI, 9.5%-55.4%), respectively.

Hui noted that the sample size for those with nonepithelioid histology may be too small to draw a conclusion of benefit, however she added that she would consider nivolumab for these patients in the salvage setting.

“The authors concluded that significant clinical benefit was observed in the epithelioid subtype with a hazard ratio of 0.71 and a 

 value of .021,” Hui said.2 “We know that nonepithelioid [disease] is a more-aggressive, chemo-resistant subtype as indicated with a steep decline in the survival curve of the chemotherapy arm of the first-line study, CheckMate-743. Therefore a lot of patients would not have made it to a subsequent line clinical trial, explaining why only 12% [of patients had this subtype] in the CONFIRM study.”

Investigators of the CheckMate-743 trial (NCT02899299) evaluated the first-line combination of nivolumab plus ipilimumab (Yervoy) versus chemotherapy in patients with malignant pleural mesothelioma. The combination was approved by the FDA as first-line treatment for adult patients with unresectable malignant pleural mesothelioma in October 2020.

Updated findings presented at the 2020 International Association for the Study of Lung Cancer showed an observed OS benefit with nivolumab plus ipilimumab over chemotherapy in those with epithelioid disease (n = 456), at 18.7 months (95% CI, 16.9-22.0) versus 16.5 months (95% CI, 14.9-20.5), respectively (HR, 0.86; 95% CI, 0.69-1.08). For those with nonepithelioid disease (n = 149) the median OS was 18.1 months (95% CI, 12.2-22.8) versus 8.8 months (95% CI, 7.4-10.2), respectively (HR, 0.46; 95% CI, 0.31-0.68).

The combination was approved by the FDA as first-line treatment for adult patients with unresectable malignant pleural mesothelioma in October 2020.

Hui concluded that there is still much to be learned about sequencing of nivolumab in the second-line setting and beyond based on results of ongoing first-line immunotherapy combination studies. “For patients who had received platinum-pemetrexed chemotherapy as first-line treatment, monotherapy nivolumab now can be considered as a treatment option in the second-line setting or third-line setting after second-line chemotherapy,” Hui said.

“As [CONFIRM] was placebo-controlled, the question is whether nivolumab provides better outcomes than second line single-agent chemotherapy or second-line gemcitabine with the VEGFR inhibitor ramucirumab [Cyramza]….What could be considered as salvage treatment if nivolumab and ipilimumab has been used in the first line setting?”

In addition to these questions, Hui stressed the importance of identifying predictive biomarkers to determine and develop other salvage treatments.

Fennel D, Ottensmeier, Califano R, et al. Nivolumab versus placebo in relapsed malignant mesothelioma: preliminary results from the CONFIRM phase 3 trial. Presented at: International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer; January 28-31, 2021; Virtual. Abstract PS01.11.

Hui R. Immune checkpoint inhibition for relapsed mesothelioma: a long time coming. Presented at: International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer; January 28-31, 2021; Virtual.

FDA approves nivolumab and ipilimumab for unresectable malignant pleural mesothelioma. FDA. October 2, 2020. Accessed January 30, 2021. 

Baas P, Scherpereel A, Nowak A, et al. First-line nivolumab + ipilimumab vs chemotherapy in unresectable malignant pleural mesothelioma: CheckMate 743. Presented at: International Association for the Study of Lung Cancer 2020 Presidential Symposium; August 8, 2020; Virtual. Abstract 3.

Articles

Nivolumab is an effective treatment approach for patients with previously treated malignant mesothelioma according to data from the phase 3 CONFIRM trial. 

Nivolumab Proven Effective for Relapsed Mesothelioma 

To identify which patients with HER2-positive breast cancer are most likely to respond to fam-trastuzumab deruxtecan-nxki (Enhertu), investigators used a novel HER2 quantitative continuous score (QCS) to provide a better objective and quantitative assessment of HER2 expression, data presented during the 2020 San Antonio Beast Cancer Symposium show.

The deep learning–based image analysis was used to generate a HER2 QCS for 151 patients with metastatic breast cancer enrolled in a phase 1 trial (NCT02564900) with varying levels of HER2 expression ranging from immunohistochemistry (IHC) 0 to IHC 3+. The use of HER2 QCS identified a greater number of HER2 expressors and demonstrated a broader stratification of efficacy between patients with high and low expressions of HER2 compared with manual pathologist scoring.

The overall response rate (ORR) was 56% and median progression-free survival (PFS) was 14.1 months for patients with tumors with HER2-high expression, regardless of scoring system. The HER2 QCS identified 67 of the 75 responders from the overall population, whereas stratification using the conventional IHC score missed 27 patients.

Of the 65 patients identified as having HER2-low–expressing tumors by conventional HER2 IHC scoring, 42% of patients treated with trastuzumab deruxtecan had a response and the median PFS was 11.0 months. When investigators used HER2 QCS, the same 65 responders identified as having low HER2 expression were further stratified into a subgroup of QCS-high and QCS-low patients. HER2 QCS was able to identify 21 of the 27 responders missed by the conventional IHC score and as a result the response rate increased to 53%, with a median PFS of 14.5 months.

Similarly, these results led to the identification of patients less likely to respond to trastuzumab deruxtecan. With only 6 responders missed, those patients in the QCS-low group had an ORR of 26% and a median PFS of 8.6 months.

“The ability to identify patients in the HER2-low group who will benefit from HER2-targeted treatment is critical for a patient population that would otherwise not be treated with anti-HER2 therapy,” Mark Gustavson said in a presentation. Gustavson is director of translational research, oncology research and development for AstraZeneca Pharmaceuticals, which develops the assessment tool and jointly develops the assessment tool with Daiichi Sankyo, Inc.

Trastuzumab deruxtecan, a HER2-directed antibody and topoisomerase inhibitor conjugate was approved in December 2019 for the treatment of patients with unresectable or metastatic HER2-positive breast cancer following treatment with at least 2 prior anti-HER2–based regimens.

 In data from the DESTINY-Breast 01 trial (NCT03248492), patients with low HER2 expression (n = 43) had an ORR of 44.2%, showing the agent’s promise a population that historically does not benefit from HER2-targeted therapy.

Manual pathologist assessed HER2 protein expression classifies tumors by the percentage of tumor cells with highest intensity and completeness of staining. Low HER2 expression is defined as IHC 1+ or IHC 2+/ISH−. As limited options are available to patients in this category, investigators developed a scoring system using artificial intelligence (AI)–based image and data analysis to better identify patients with low-level expression in anticipation of trastuzumab deruxtecan’s continued efficacy in this population.

Deep learning models trained on commercial breast cancer samples to detect membrane, cytoplasm and nuclei of all tumor cells. The HER2 QCS was trained using pathologists’ annotations and was validated on unseen data. Optical density (OD), or level of brown stain intensity, was computed on detected membranes to derive features that could be linked to survival prediction.

In the identification of patients with high expression of HER2, investigators used a cellular ODq10 cutoff of greater than 8 in at least 90% of cells for patients to be positive. In the subgroup analysis of the 65 responders with HER2 low expression as determined by IHC, the cellular ODq10 cutoff was determined to be greater than 7.4 in at least 90% of cells to be positive.

“These data establish a clinical proof-of-concept demonstrating that use of HER2 QCS can potentially enhance prediction of patient outcome with [trastuzumab deruxtecan] by increasing the sensitivity and specificity of identification of patients with high and low HER2 expression,” Gustavson said.

Of note, investigators also determined that patients with low or negative HER2 expression response to treatment with trastuzumab deruxtecan was driven by a majority of tumor cells expressing a minimal amount of HER2 rather than a minority of cells that express higher levels of HER2.

A final factor that was assessed was role of spatial proximity for positive cells. Patients with 95% of cells having an OD value above the determined threshold were considered to have a homogenous HER2 distribution pattern (n = 36; 55.4%). Those with less than 95% of cells meeting the threshold had a heterogenous HER2 distribution pattern (n = 29; 44.6%).

Similar efficacy was observed with these subgroups as compared with best performing cutoffs. The ORR for the homogenous group was 53% with a median PFS of 14.8 months. The heterogenous group had an ORR of 28% with a median PFS of 8.6 months.

Further validation of the HER2 QCS is underway. Additional investigation of trastuzumab deruxtecan is also ongoing in the phase 3 DESTINY-Breast04 trial (NCT03734029) for patients with HER2-low–expressing tumors.

1. Gustavson M, Haneder S, Spitzmueller A, et al. Novel approach to HER2 quantification: digital pathology coupled with AI-based image and data analysis delivers objective and quantitative HER2 expression analysis for enrichment of responders to trastuzumab deruxtecan (T-DXd; DS-8201), specifically in HER2-low patients. Poster presented at: 2020 San Antonio Breast Cancer Symposia; December 8-11, 2020; virtual. Abstract PD6-01.

2. FDA approves fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive breast cancer. FDA. Updated December 20, 2019. Accessed December 10, 2020. 

Modi S, Saura A, Yamashita T, at al; DESTINY-Breast 01 Investigators. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. 

. 2020;382(7):610-621. doi:10.1056/NEJMoa1914510

To identify which patients with HER2-positive breast cancer are most likely to respond to fam-trastuzumab deruxtecan-nxki, investigators used a novel HER2 quantitative continuous score to provide a better objective and quantitative assessment of HER2 expression, data presented during the 2020 San Antonio Beast Cancer Symposium show. 

Better Prediction of Response to Trastuzumab Deruxtecan Analyzed in HER2-Positive Breast Cancer

In the phase 3 UNITY-CLL study, ublituximab in combination with umbralisib (U2) demonstrated synergistic activity in patients with chronic lymphocytic leukemia compared with standard of care chemoimmunotherapy irrespective of prior treatment.

Results for the study of the CD20-targeting compound ublituximab and PI3Kδ-targeting agent umbralisib were presented during the American Society of Hematology (ASH) Virtual Annual Meeting.

At a median follow-up of 36.7 months, U2 significantly prolonged progression-free survival (PFS) compared with obinutuzumab (Gazyva) plus chlorambucil across subgroups. In the intention-to-treat population the median PFS was 31.9 months (95% CI, 28.2-35.8) versus 17.9 months (95% CI, 16.1-22.6), respectively (HR, 0.546; 95% CI, 0.413-0.720; 

 < .0001). The 24-month PFS rates were 60.8% and 40.4%, respectively.

In patients who were treatment-naïve at the time of enrollment, the median PFS was 38.5 months (95% CI, 33.2–not evaluable) with U2 compared with 26.1 months (95% CI, 19.4-33.1) with the obinutuzumab combination (HR, 0.482; 95% CI, 0.316-0.736; 

 < .001). The 24-month PFS rates were 76.6% and 52.1%, respectively.

For the subgroup of patients who received a median of 2 prior therapies (range, 1-9), those randomized to the U2 cohort also had a PFS benefit with U2 compared with obinutuzumab plus chlorambucil (19.5 vs 12.9 months, respectively; HR, 0.601; 95% CI, 0.415-0.869; 

Bruton tyrosine kinase [BTK] and BCL-2 [B-cell lymphoma] inhibitors have dramatically changed the therapeutic landscape of CLL, but not all patients are candidates for these agents and mechanisms of resistance have already been identified,” said global study chair, John G. Gribben, DSc, FRCP, FRCPath, FMedSci, during a presentation of the data. “I think PI3Kδ inhibitors offer a distinct mechanism of action from all the BTK and BCL-2 inhibitors and have demonstrated promising activity in the relapsed/refractory CLL setting.” Gribben is a professor of experimental cancer medicine, director of both the Experimental Cancer Medicine Centre and Stem Cell Transplantation at Saint Bartholomew’s Hospital, Queen Mary’s School of Medicine, University of London.

In addition to its efficacy, the U2 regimen has a favorable safety profile and exhibited low rates of immune-mediated toxicities that are typically associated with other PI3Kδ inhibitors, including diarrhea, colitis, pneumonia, and hepatic toxicity. In previously untreated patients these toxicities lead to discontinuation rates of over 50%.

In total, 421 patients with treatment-naïve or relapsed/refractory CLL were included in the primary analysis of the UNITY-CLL trial (NCT02612311); 57% of patients were treatment-naïve and 43% had relapsed/refractory CLL.

Umbralisib was given orally at 800 mg once-daily until progression or treatment discontinuation. Ublituximab was administered intravenously at 900 mg on days 1/2 (150 mg on day 1 followed by 750 mg on day 2), 8, and 15 of cycle 1; day 1 of cycles 2 to 6, and on day 1 every 3 cycles after cycle 6. Obinutuzumab was given intravenously at 1000 mg on days 1/2 (100 mg on day 1 followed by 900 mg on day 2), 8, and 15 of cycle 1; day 1 of cycles 2 to 6. Chlorambucil was given orally at 0.5 mg/kg on day 1 and 15 of cycles 1 to 6. Each cycle was 28 days.

The primary end point was independent review committee (IRC)-assessed PFS and key secondary end points included IRC-assessed overall response rate (ORR), complete response (CR), and safety assessed from the first dose until 30 days after the last dose.

The ORR for 210 patients treated in the U2 cohort was 83.3% compared with 68.7% for the 211 patients in the obinutuzumab arm (

 < .001). Of the responders, 5% achieved a CR or CR with incomplete marrow recovery and 79% had a partial response with U2 versus 1% and 67%, respectively, with obinutuzumab.

In stratified analysis, the ORRs were 84%, 82%, and 57% for patients in the U2 cohort who were treatment naïve, were previously treated, and those who had prior treatment with a BTK inhibitor, respectively. The ORRs were 78%, 57%, and 25% for those treated with obinutuzumab.

“Responses [observed] with U2 were durable with 62% of patients maintaining response at 2 years and a 93% disease control rate was achieved using the U2 regimen,” said Gribben. The median treatment exposure for U2 was 21 months compared with 5 months for obinutuzumab and chlorambucil, Gribben added. At the time of follow-up treatment was ongoing for 77 patients (37%) with U2.

In a review of the safety analysis, Gribben noted that continuous treatment with U2 resulted in over 4-fold longer exposure and reporting period for the regimen compared with obinutuzumab and chlorambucil. Grade 3/4 adverse events of clinical interest for U2 versus the chemoimmunotherapy regimen included elevated alanine aminotransferase (8.3% vs 1.0%), elevated aspartate aminotransferase (5.3% vs 2.0%), noninfectious colitis (1.9% vs 0%), infectious colitis (0.5% vs 0.5%), pneumonitis (0.5% vs 0%), rash (2.4% vs 0.5%), and opportunistic infections (5.8% vs 1.5%). AEs led to treatment discontinuation in 35 patients (17%) and 16 patients (8%), respectively.

“Focusing in on those grade 3 and 4 adverse events and looking at the treatment-naïve versus patients who were previously treated, diarrhea occurred slightly more frequently in the treatment-naïve patient population [13.8% vs 10.0%], but neutropenia was more common in those patients who were previously treated [24.1% vs 40.0%]. Other adverse events were relatively rare,” Gribben said.

TG Therapeutics Inc, the developer of the agents, plans to complete a new drug application submission for the U2 combination in CLL in the first half of 2021.3 The company initiated a rolling submission of a biologics application with the FDA based on these data.

1. Gribben JG, Jurczak W, Jacobs R, et al. Umbralisib plus ublituximab (U2) is superior to obinutuzumab plus chlorambucil (O+Chl) in patients with treatment naïve (TN) and relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): results from the phase 3 Unity-CLL Study. Presented at: American Society of Hematology Meeting and Exposition; December 5-8, 2020; Virtual. Abstract 543. Accessed December 7, 2020. https://ash.confex.com/ash/2020/webprogram/Paper134783.html

2. Lunning M, Vose J, Nastoupil L, et al. Ublituximab and umbralisib in relapsed/refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia. 

. 2019;134(21):1811-1820. doi:10.1182/blood.2019002118

3. TG Therapeutics announces pivotal data from the UNITY-CLL and UNITY-NHL clinical trials presented at the 62nd American Society of Hematology Annual Meeting. News release. TG Therapeutics, Inc. December 7, 2020. Accessed December 7, 2020. https://bit.ly/3mVFbFb

4. TG Therapeutics initiates rolling submission of biologics license application to US Food and Drug Administration for ublituximab in combination with umbralisib as a treatment for patients with chronic lymphocytic leukemia. News release. TG Therapeutics, Inc. December 1, 2020. Accessed December 7, 2020. https://bit.ly/3muaDKm

In the phase 3 UNITY-CLL study, ublituximab in combination with umbralisib demonstrated synergistic activity in patients with chronic lymphocytic leukemia compared with standard of care chemoimmunotherapy irrespective of prior treatment.

Ublituximab Doublet Bests Chemoimmunotherapy in Chronic Lymphocytic Leukemia

Early data in mouse models have demonstrated that the novel approach of providing CD2 costimulation to chimeric antigen receptor (CAR) T cells in 

 could reeestablish the efficacy of treatment in patients with CD58 mutations, suggesting CARs engineered to overcome CD58 loss may provide an alternative option for the treatment of patients with large B-cell lymphomas who do not respond to immunotherapy, according to Robbie G. Majzner, MD, who presented the findings at the 2020 ASH Annual Meeting.

Anti-CD19 CAR T-cell therapy produces durable remission in approximately 40% of patients with B-cell lymphomas, however strategies to overcome mechanisms of resistance, including immune escape, are needed for patients.

 One such identified genetic event is CD58 inactivity. CD58 is the receptor of the CD2 molecule expressed by T cells and natural killer cells and its expression is necessary for T-cell– and natural killer cell-mediated cytotoxicity.

 mutations or loss are common and occur in 21% of patients with diffuse large B-cell lymphoma (DLBCL) and CD58 protein expression is deregulated in approximately 67% of all patients with DLBCL.

In results of a study of 51 patients treated with axicabtagene-ciloleucel (axi-cel; Yescarta), 25% of patients did not have a fully functioning version of the CD58 protein and that these patients did not have a long-term response to axi-cel.

 alteration—either a mutation or absence by next generation sequencing or immunohistochemistry—the median progression-free survival was 3.12 months for patients versus not reached for those with 

=.0043) at a median follow-up of 12.4 months.

“[The outcomes for] patients who don’t obtain durable, complete responses outcome is really, really poor, [with a median] overall survival of a less than 200 days,” said Majzner, an assistant professor of pediatrics in the Division of Hematology and Oncology at Stanford University School of Medicine.

Further, he noted that when examining the data of the types of responses elicited in patients with DLBCL, less than 30% of those with 

 alterations had complete responses to treatment with axi-cel compared with almost 80% of patients with 

 wild-type disease. Partial responses were seen more in those with 

-altered DLBCL (approximately 60%) compared with 

“We wanted to understand the biology of what CD58 is providing for CAR T cells,” Majzner said. “We know that CAR T-cell [therapy] is able to induce long-term remission in patients, we feel that if we could just get this initial response rate up and find that find the mechanisms of resistance and engineer around them, we could cure more patients,” he said.

To test this hypothesis, investigators took a B-cell leukemia line and used CRISPR technology to create a CB58 knockout version of the gene. Next, they exposed CAR T cells including a 1928 axi-cel–like CAR and a 19BBC tisagenlecleucel (Kymriah)-like CAR. “This is a killing assay and CAR T cells lose their ability to kill the tumor cell when CD58 is knocked out,” Majzner said.

In mice models, those that were inoculated with 

 wild-type leukemia and treated with the axi-cel–like product had long-term disease control compared with those who were treated with CD58 knockout leukemia and experienced initial disease control and response, but ultimately relapsed and died from disease progression.1 Similar data were observed in those treated with a tisagenlecleucel-like product.

To overcome CD58 loss, investigators set their focus on reengineering CARs to integrate CD2 signaling to reestablish efficacy of the T cells. Investigators determined that the cross-linking between CD2 and CD58 played a role in driving CAR signaling and cytoskeletal rearrangements

that drive T-cell function needed to kill target tumor cells.

“This data was very surprising to us, to see how important CD2 costimulation turned out to be for CAR T cells,” Majzner said. “We always considered CAR T cells to be already endowed with costimulation and what this data tells us is that other costimulators on the surface of tumor cells really matter and can drive that T-cell function.”

Investigators engineered CARs to integrate CD2 signaling in 

 set up, did we have a significant tumor control of the CD58 knockout tumor cells and a significant prolongation of survival,” Majzner said. At the time of presentation, investigators noted that clinical trials could be underway within in 1 to 2 years.

Investigators believe that the modified treatment could significantly increase the number of patients who are likely to benefit from axi-cel therapy and could have an effect on immunotherapy research in other malignancies where 

1. Majzner RG, Frank MJ, Mount C, et al. CD58 aberrations limit durable responses to CD19 CAR in large B cell lymphoma patients treated with axicabtagene ciloleucel but can be overcome through novel CAR engineering. Presented at: 2020 American Society of Hematology Meeting and Exposition; December 4-8, 2020; virtual. Accessed December 5, 2020. 

https://ash.confex.com/ash/2020/webprogram/Paper139605.html

2. Genome editing and cellular therapies show promise for treating blood disorders, cancers. News release. American Society of Hematology. December 5, 2020. Accessed December 5, 2020. 

https://www.hematology.org/newsroom/press-releases/2020/genome-editing-and-cellular-therapies-show-promise-for-treating-blood-disorders-cancers

3. Abramson JS. Anti-CD19 CAR T-cell therapy for B-cell non-Hodgkin lymphoma. 

. 2020;34(1):29-33. doi:10.1016/j.tmrv.2019.08.003

4. Testoni M, Zucca E, Young KH, Bertoni F. Genetic lesions in diffuse large B-cell lymphomas. 

. 2015;26(6):1069-1080. doi:10.1093/annonc/mdv019

Early data in mouse models have demonstrated that the novel approach of providing CD2 costimulation to CAR T cells in trans could reeestablish the efficacy of treatment in patients with CD58 mutations

Brittany Lovely | Authors

Articles

Nivolumab Proven Effective for Relapsed Mesothelioma

Better Prediction of Response to Trastuzumab Deruxtecan Analyzed in HER2-Positive Breast Cancer

Ublituximab Doublet Bests Chemoimmunotherapy in Chronic Lymphocytic Leukemia

Novel CAR Approach Overcomes Resistance in CD58-Mutant Large B-Cell Lymphoma