The following articles have been recommended for further reading in the field of cancer immunotherapy by JITC's Interim Editor-in-Chief Dr. James L. Gulley.
“Nivolumab Plus Ipilimumab vs Nivolumab Alone in Advanced Cancers Other Than Melanoma A Meta-Analysis” by Serritella et al
JAMA Oncol. (2023)
Abstract:
Importance – Although the combination of nivolumab plus ipilimumab has unquestionable benefit over nivolumab monotherapy in advanced melanoma, currently no summative analyses have compared the combination with nivolumab monotherapy for advanced cancers other than melanoma.
Objective – To examine whether the addition of ipilimumab to standard-dose nivolumab safely improves clinical outcomes in patients with advanced cancers other than melanoma.
Data Sources – Electronic databases (PubMed, EBSCO Information Services, Embase, and Cochrane Library) were systematically searched for studies of standard-dose nivolumab plus ipilimumab vs nivolumab alone in the treatment of advanced cancers other than melanoma published from database inception to October 31, 2022.
Study Selection – Eight studies (total patients, 1727; nivolumab plus ipilimumab group, 854; nivolumab monotherapy group, 873) met the selection criteria. Patients had squamous cell lung cancer, non–small cell lung cancer with programmed death ligand 1 level of 1% or higher, small cell lung cancer, pleural mesothelioma, urothelial carcinoma, esophagogastric carcinoma, sarcoma, or glioblastoma multiforme.
Data Extraction and Synthesis – For comparison of overall survival (OS) and progression-free survival (PFS) outcomes, estimation of log(hazard ratios [HRs]) and SEs was initially performed for OS and PFS of each included study based on summary statistics extracted from individual Kaplan-Meier curves. Inverse-variance weighting was then used to compute pooled HRs (95% CIs). For comparison of dichotomous data (treatment-related grade 3 to 4 adverse events and discontinuations), odds ratios (ORs) were used, and the Mantel-Haenszel method was used to estimate pooled ORs (95% CIs).
Results – Treatment with nivolumab plus ipilimumab was not associated with improvement in OS over treatment with nivolumab alone (pooled HR, 0.95; 95% CI, 0.85-1.06; P = .36), with 4 of the 8 studies having numerically lower median OS with the combination. Nivolumab plus ipilimumab combination therapy was associated with marginal, but not clinically meaningful, improvement in PFS over nivolumab alone (pooled HR, 0.88; 95% CI, 0.79-0.98; P = .02). The combination was associated with substantially higher treatment-related grade 3 to 4 adverse events (pooled OR, 1.84; 95% CI, 1.47-2.31; P < .001) and treatment-related discontinuations (pooled OR, 1.96; 95% CI, 1.44-2.65; P < .001). This finding was recapitulated in meta-analyses of individual grade 3 to 4 adverse events of hepatotoxicity, gastrointestinal toxicity, pneumonitis, endocrine dysfunction, dermatitis, fatigue.
Conclusions and Relevance – In this meta-analysis of 8 advanced cancers other than melanoma, the differences detected in OS and PFS between nivolumab plus ipilimumab and nivolumab were not clinically meaningful (even though statistical significance was detected in PFS). Treatment-related higher-grade toxicity and discontinuations were substantially higher with the combination therapy. The data indicate that investigations of anti–programmed death 1 (PD1) plus anti–cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) therapies in any nonmelanoma advanced cancer should be conducted along with anti-PD1 monotherapy to ensure that the net effect of the addition of anti-CTLA-4 to anti-PD1 can be clearly established for that cancer and setting and that unnecessary CTLA-4 inhibition with related toxic effects (both clinical and financial) can be avoided.
Why this matters: While CTLA-4 blockade added to PD-1 inhibition has been successfully used in melanoma, its use is associated with a higher proportion of patients with immune related adverse events (irAEs), and more severe irAEs than PD-1 inhibition alone. This meta-analysis of 1,727 patients from randomized non-melanoma studies suggests that there is no clinically meaningful impact of adding CTLA-4 blockade to PD-1 inhibition in these patients and that the combination was associated with increased irAEs.
“Association Between Duration of Immunotherapy and Overall Survival in Advanced Non–Small Cell Lung Cancer” by Sun et al
JAMA Oncol. (2023)
Abstract:
Importance – For patients with advanced non–small cell lung cancer (NSCLC) treated with frontline immunotherapy-based treatment, the optimal duration of immune checkpoint inhibitor (ICI) treatment is unknown.
Objective – To assess practice patterns surrounding ICI treatment discontinuation at 2 years and to evaluate the association of duration of therapy with overall survival in patients who received fixed-duration ICI therapy for 2 years vs those who continued therapy beyond 2 years.
Design, Setting, and Participants – This retrospective, population-based cohort study included adult patients in a clinical database diagnosed with advanced NSCLC from 2016 to 2020, who received frontline immunotherapy-based treatment. The data cutoff was August 31, 2022; data analysis was conducted from October 2022 to January 2023.
Exposures – Treatment discontinuation at 2 years (between 700 and 760 days, fixed duration) vs continued treatment beyond 2 years (greater than 760 days, indefinite duration).
Main Outcomes and Measures – Overall survival from 760 days was analyzed using Kaplan-Meier methods. Multivariable Cox regression that adjusted for patient-specific and cancer-specific factors was used to compare survival beyond 760 days between the fixed-duration group and the indefinite-duration group.
Results – Of 1091 patients in the analytic cohort who were still on ICI treatment at 2 years after exclusion criteria for death and progression were applied, 113 patients (median [IQR] age, 69 [62-75] years; 62 [54.9%] female; 86 [76.1%] White) were in the fixed-duration group, and 593 patients (median [IQR] age, 69 [62-76] years; 282 [47.6%] female; 414 [69.8%] White) were in the indefinite-duration group. Patients in the fixed-duration group were more likely to have a history of smoking (99% vs 93%; P = .01) and be treated at an academic center (22% vs 11%; P = .001). Two-year overall survival from 760 days was 79% (95% CI, 66%-87%) in the fixed-duration group and 81% (95% CI, 77%-85%) in the indefinite-duration group. There was no statistically significant difference in overall survival between patients in the fixed-duration and indefinite-duration groups, either on univariate (hazard ratio [HR] 1.26; 95% CI, 0.77-2.08; P = .36) or multivariable (HR 1.33; 95% CI, 0.78-2.25; P = .29) Cox regression. Approximately 1 in 5 patients discontinued immunotherapy at 2 years in the absence of progression.
Conclusions and Relevance – In a retrospective clinical cohort of patients with advanced NSCLC who were treated with immunotherapy and were progression-free at 2 years, approximately only 1 in 5 discontinued treatment. The lack of statistically significant overall survival advantage for the indefinite-duration cohort on adjusted analysis provides reassurance to patients and clinicians who wish to discontinue immunotherapy at 2 years.
Why this matters: PD-1 inhibition has activity in lung cancer, however, only a small minority are progression free after 2 years. In this retrospective study, the authors demonstrate that among this small subset of exceptional responders, there is a lack of statistically significant OS advantage for patients with indefinite treatment vs. those who had ICI stopped at two years providing reassurance to patients and clinicians who choose to discontinue ICI.
“Base-Edited CAR7 T Cells for Relapsed T-Cell Acute Lymphoblastic Leukemia” by Chiesa et al
N Engl J Med (2023)
Abstract:
Background – Cytidine deamination that is guided by clustered regularly interspaced short palindromic repeats (CRISPR) can mediate a highly precise conversion of one nucleotide into another - specifically, cytosine to thymine - without generating breaks in DNA. Thus, genes can be base-edited and rendered inactive without inducing translocations and other chromosomal aberrations. The use of this technique in patients with relapsed childhood T-cell leukemia is being investigated.
Methods – We used base editing to generate universal, off-the-shelf chimeric antigen receptor (CAR) T cells. Healthy volunteer donor T cells were transduced with the use of a lentivirus to express a CAR with specificity for CD7 (CAR7), a protein that is expressed in T-cell acute lymphoblastic leukemia (ALL). We then used base editing to inactivate three genes encoding CD52 and CD7 receptors and the β chain of the αβ T-cell receptor to evade lymphodepleting serotherapy, CAR7 T-cell fratricide, and graft-versus-host disease, respectively. We investigated the safety of these edited cells in three children with relapsed leukemia.
Results – The first patient, a 13-year-old girl who had relapsed T-cell ALL after allogeneic stem-cell transplantation, had molecular remission within 28 days after infusion of a single dose of base-edited CAR7 (BE-CAR7). She then received a reduced-intensity (nonmyeloablative) allogeneic stem-cell transplant from her original donor, with successful immunologic reconstitution and ongoing leukemic remission. BE-CAR7 cells from the same bank showed potent activity in two other patients, and although fatal fungal complications developed in one patient, the other patient underwent allogeneic stem-cell transplantation while in remission. Serious adverse events included cytokine release syndrome, multilineage cytopenia, and opportunistic infections.
Conclusions – The interim results of this phase 1 study support further investigation of base-edited T cells for patients with relapsed leukemia and indicate the anticipated risks of immunotherapy-related complications. (Funded by the Medical Research Council and others; ISRCTN number, ISRCTN15323014.)
Why this matters: The authors show that these CRISPR edited CAR-T can be an off-the-shelf platform leading to deep responses for patients with T-cell acute lymphoblastic leukemia. This universal CAR-T could decrease the time to cell therapy while maintaining an active regimen. While only the initial 3 subjects were reported in this study from the UK, this CAR-T had potent activity allowing for allogeneic stem-cell transplantation while in remission.
“Spatial predictors of immunotherapy response in triple-negative breast cancer” by Wang et al
Nature (2023)
Abstract:
Immune checkpoint blockade (ICB) benefits some patients with triple-negative breast cancer, but what distinguishes responders from non-responders is unclear1. Because ICB targets cell–cell interactions2, we investigated the impact of multicellular spatial organization on response, and explored how ICB remodels the tumour microenvironment. We show that cell phenotype, activation state and spatial location are intimately linked, influence ICB effect and differ in sensitive versus resistant tumours early on-treatment. We used imaging mass cytometry3 to profile the in situ expression of 43 proteins in tumours from patients in a randomized trial of neoadjuvant ICB, sampled at three timepoints (baseline, n = 243; early on-treatment, n = 207; post-treatment, n = 210). Multivariate modelling showed that the fractions of proliferating CD8+TCF1+T cells and MHCII+ cancer cells were dominant predictors of response, followed by cancer–immune interactions with B cells and granzyme B+ T cells. On-treatment, responsive tumours contained abundant granzyme B+ T cells, whereas resistant tumours were characterized by CD15+ cancer cells. Response was best predicted by combining tissue features before and on-treatment, pointing to a role for early biopsies in guiding adaptive therapy. Our findings show that multicellular spatial organization is a major determinant of ICB effect and suggest that its systematic enumeration in situ could help realize precision immuno-oncology.
Why this matters: By mapping the multicellular tumor microenvironment in TNBC, the authors uncovered key immune checkpoint inhibitor (ICI) response predictors and showed that ICI distinctively remodels tumor structure. Not surprisingly, the predictors of response include MHC expression and the presence of CD8+TCF1+ T-cells. Systematically analyzing the impact of immunotherapy in a way that preserves the tumor architecture and spatial organization may provide a valuable tool for precision immunotherapy.