Recent immunotherapy trials for cancer
Our AI provides a round-up of recent immunotherapy RCTs available on PubMed
The individual reports below - including each headline - were generated automatically by our machine-reading software from recent research on immunotherapy trials reported on PubMed.
The headlines in italic are generated by our abstractive engine. The longer synopses use our extractive engine, and consist of automatically extracted highlights from the original texts, with some subclause truncation, transitional phrase removal, and rewriting in the third person.
A clinical trial of vorinostat, tamoxifen and pembrolizumab in breast cancer patients with ER-positive breast cancer has met its primary and secondary endpoints.
Manuela Terranova-Barberio et al. (2020) described how exhausted T cell signature predicts immunotherapy response in ER-positive breast cancer. Responses to immunotherapy are uncommon in estrogen receptor (ER)-positive breast cancer. The low response rate is consistent with other immune checkpoint studies enrolling. Treatment significantly reduced activated Tregs in the tumor microenvironment. The proportion of responders (CR, PR and SD > 6 months) and duration of response was markedly improved in patients with an increased number of exhausted cytotoxic CD8+ T lymphocytes. A causal, rather than bystander, role of the HDACi in the response to the immune checkpoint inhibitor-HDACi combination is supported by the significant correlation between histone H3 and lysine acetylation.
The research involved 34 patients. The researchers’ results claim to support prior research in this topic: “Our data is consistent with reports that the increase of Tregs residing in tumors is an epigenetic phenomenon, rather than circulating T-cells infiltrating the tumor. Treatment was correlated with response in patients with high levels of partially exhausted CTLs,” Terranova-Barberio said. However, “The trial was halted after enrolling 34 of the 87 patients originally planned, due to its limited efficacy in an unselected patient population. Responder T-cell exhaustion was detectable, despite a very low overall immune cell infiltration,” observe the investigators.
Glioblastoma is the most common type of brain cancer for which there is currently no cure.
A team led by David Reardon at the AUSL–IRCCS Institute of Neurological Sciences (2020) reported on effect of nivolumab vs bevacizumab in patients with recurrent glioblastoma. Grade 3/4 treatment-related adverse events (TRAEs) were similar between groups. No unexpected neurological TRAEs or deaths due to TRAEs. Toxic effects were consistent with the known safety profiles of nivolumab and bevacizumab. The MGMT promoter was methylated in 23.4% and 22.7%, unmethylated in 32.1% and 36.2%, and not reported in remaining patients. The CheckMate 143 randomized clinical trial is the first phase 3 study investigating the use of a programmed death-1 inhibitor in patients with recurrent glioblastoma.
439 patients with glioblastoma at first recurrence following standard radiation were involved in the study. Discussing potential shortcomings, “Study limitations include the small number of patients in the subgroup analyses, lack of standardized MGMT promoter methylation status assessment, and use of archival tissue collected at the time of initial diagnosis for biomarker analyses,” they observe. Reardon and colleagues advocate that a study of nivolumab in combination with radiotherapy and temozolomide in patients with newly diagnosed glioblastoma with methylated MGMT promoter is ongoing. Data and code are available from: https://www.bms.com/researchersand-partners/independent-research/data-sharingrequest-process.html.
Bevacizumab, an anti-PDL-1 checkpoint inhibitor, has been added to the treatment of colorectal cancer by Bristol-Myers Squibb.
Carlotta Antoniotti et al. (2020) reported in ‘AtezoTRIBE’ that new data in favour of the upfront treatment with triplet plus bevacizumab in mCRC were reported by the TRIBE2 study. When choosing the upfront exposure to the three cytotoxics, the feasibility and the efficacy of treatments given after disease progression were not impaired. AtezoTRIBE is a prospective, open label, phase II, comparative trial in which initially unresectable and previously untreated mCRC patients, irrespective of microsatellite status, are randomized in a 1:2 ratio. The primary objective of this study is to evaluate the efficacy of the addition of atezolizumab to FOLFOXIRI.
201 patients were included in the study. The results claim to back up previous work in this subject: “The phase III TRIBE study compared the triplet FOLFOXIRI plus bevacizumab with the doublet in previously untreated mCRC patients. It showed a significant benefit from the intensification of the chemotherapy backbone in terms of progression-free survival 0.77, RECIST response rate and overall survival,” Antoniotti claimed.
Two breast cancer vaccines, AE37 and GP2, may be able to prevent recurrence in some patients, according to the results of a phase II trial.
Tommy Brown et al. (2020) studied prospective, randomized, single-blinded, multi-center phase II trial of two HER2peptide vaccines, GP2 and AE37, in breast cancer patients to prevent recurrence. Vaccines targeting immunogenic HER2 peptides may provide benefit via immune-mediated cancer cell elimination. The primary objectives of this study were to determine if AE37 in combination with GM-CSF vaccination improves the DFS in any level HER2 expressing, node positive or high-risk node negative breast cancer patients. Despite progress via early detection and improved treatment, breast cancer recurrence remains a significant problem.
There were 456 patients involved in the study. However, “A limitation of this analysis is the per-treatment nature possibly affecting the external validity of the data. Even with the exclusion of these early recurrence and second malignancy patients, there was still no significant differences between the group demographics,” admit the authors.
Oral cryotherapy (OC) did not reduce the incidence of severe oral mucositis, oral pain, or opioid use in children undergoing hematopoietic stem cell transplantation (HSCT), a trial in Sweden has found.
Tove Kamsvåg et al. (2020) reported on prevention of oral mucositis with cryotherapy in children undergoing hematopoietic stem cell transplantations. Oral mucositis is a common adverse effect of antineoplastic treatment. Twenty-six children were randomized to the OC group and 23 to the control group. The team could not find that OC reduced the grade of OM, oral pain, or use of opioids in children undergoing HSCT in this study. OM is reported to be one of the most painful and debilitating side effects of cancer treatment in pediatric patients. OC has been shown to be useful for patients undergoing HSCT; conclusive studies in children are missing.
53 children were included in the analysis. The authors’ conclusions potentially confirm prior research in this field: “This is consistent with the course of neutropenia and coincides with the CRP peak, affirming previous studies on OM during HSCT. We found relatively high scores for oral pain despite high doses of opioids,” Kamsvåg said. They propose that the heterogeneity of diagnoses and conditioning regimens, age, and the low compliance with OC makes it difficult to draw any firm conclusions. For future studies of OC in children, it would be preferable to have a more homogenous sample. The authors have provided data and code at: https://doi.org/10.1007/s00520-019-05258-2.
The order of application of cyclophosphamide-busulfan before allogeneic hematopoietic cell transplantation in patients with hematological malignancy has impact on outcome.
A group led by Claire Seydoux of the Divisions of Hematology and Internal Medicine (2020) described busulfan-cyclophosphamide versus cyclophosphamide-busulfan as conditioning regimen before allogeneic hematopoietic cell transplantation. The combination of busulfan and cyclophosphamide is a frequently used established myeloablative conditioning regimen before allogeneic cell transplantation. Cy-induced toxicity has been associated with nonrelapse mortality and decreased survival in clinical studies. A total of 33 patients were randomized to the standard group and 37 to the experimental group. Studies have shown that Bu affects the hepatic metabolism of Cy and may increase liver toxicity when given in this order. With the introduction of intravenous Bu, associated with reduced liver complications and mortality, these considerations influencing the order of application no longer apply.
70 patients with hematological malignancy were included in the study. The researchers’ findings appear to strengthen prior research in this area: “The order of application of Cy and Bu may have an impact on short- and long-term toxicity and outcome after allo-HCT. Our study is in line with previous retrospective and animal studies,” Seydoux suggested. However, “Screening failure was 39% excluding patients with preexisting liver abnormalities, thus assuring inclusion of patients with normal liver function. Patient accrual was low because of tendency to increasingly use reduced intensity regimens. Randomization was not blinded; however, bias in measuring liver function tests or NRM is unlikely,” acknowledge the authors.
A new stem-cell product, ATIR101, reduces the risk of graft-versus-host disease in patients with acute leukemia.
Denis Roy et al. (2020) studied how ATIR101 administered after T-cell-depleted haploidentical HSCT reduces NRM and improves overall survival in acute leukemia. Despite recent translational achievements, allogeneic hematopoietic stem-cell transplantation still represents the only established curative option for most high-risk patients. High incidences of chronic GvHD, and high relapse rates remain well-known obstacles to the overall improvement of outcome after allogeneic HSCT. In the absence of a defined standard approach to haploidentical HSCT, an observational registry study was undertaken to provide control groups matching the inclusion/exclusion criteria of the ATIR101 study. The rise of haploidentical HSCT is mostly associated with the rise in T-cell-replete strategies such as posttransplant cyclophosphamide. ATIR101 is an adjunctive cellular therapy, selectively depleted of recipient-alloreactive T cells, which is administered after TCD-haplo.
There were 23 patients with acute leukemia and compared with an observational included in the study. The authors’ conclusions appear to support previous work in this area: “composite endpoints such as GRFS reflecting disease status and quality of life are gaining importance in HSCT. Results for control study groups reported in the present study are in line with those from the CIBMTR with 1-year survival for malignant diseases receiving MUD of 68%, 60% for MMUD, and 59% for UCB,” Roy suggested. Data and code are available from: https://doi.org/10.1038/s41375-020-0733-0.
Mesenchymal stem cells (MSCs) promote platelet engraftment and decrease severe acute GVHD without increasing relapse rate in patients undergoing haploidentical peripheral blood stem cell transplantation (haplo-PBSCT).
Xiaoning Wang et al. (2020) noted that hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for malignant and non-malignant hematological diseases. No randomized controlled studies have been conducted to confirm the impact of pre-infusion single-dose MSCs on engraftment, GVHD, or relapse rate in patients undergoing haploidentical peripheral blood stem cell (PBSC) transplantation. Pre-infusion single-dose Mesenchymal stem cells promote platelet engraftment and decrease severe acute graft versus host disease without increasing relapse rate.
50 patients with acute leukemia or myelodysplastic syndrome were randomly included in the study. The researchers’ results claim to contrast earlier research in the field: “Gao et al. reported that the repeated infusion of MSCs inhibited chronic GVHD in HLA haploidentical HSCT without increasing the relapse rates. In contrast, the current study, a pre-infusion single dose of M.SCs. 4 to 6 hours before infusion of PBSCs decreased severe acute GvHD, which was inconsistent with Liu et al.'s report.” The researchers observe that “This study showed that a single pre-infusion dose of MSCs could promote platelet engraftment and decrease severe acute GVHD without relapse.” They admit that they did not monitor changes in immune cell subsets or cytokine levels after a single infusion of MSCs. The number of cases was small, and further studies with larger patient cohorts are needed.
The HPV-16/18 AS04-adjuvanted vaccine had no significant effect on acquiring high-risk HPV (HR-HPV) infection after treatment in women who underwent surgery for cervical cancer.
A team at the Department of Epidemiology led by Shuang Zhao (2020) reported on impact of HPV-16/18 AS04-adjuvanted vaccine on preventing subsequent infection and disease after excision treatment. It is widely acknowledged that Human Papillomavirus prophylactic vaccine could prevent new infections and their associated lesions among women who are predominantly HPV-naive at vaccination. A prospective study, evaluating the clinical effectiveness of HPV vaccine in reducing CIN2+ recurrent disease, suggested that quadrivalent HPV vaccination could reduce the risk of subsequent HPV related high-grade cervical intraepithelial neoplasia by 81.2%. Women after treatment for CIN remain at a substantially increased risk of subsequent cervical cancer. This is the first analysis in China to evaluate the efficacy of HPV 16/18 AS04-adjuvanted vaccination on the relapse of cervical precancerous lesions or cancers. The researchers observed a significant effect of vaccination on acquiring 14 high-risk HPV (HR-HPV) infection after treatment.
3 expert gynecological pathologists were included in the study. The authors’ findings potentially substantiate what was previously known about this subject: “Analysis from a large clinical trial in Costa Rica indicated significant vaccine efficacy against the development of new infection associated with HPV31/33/45. Vaccine efficacy against HPV16/18 new infection was positive but didn’t reach statistical significance,” Zhao claimed. Discussing possible shortcomings, “The subgroup of women who underwent excision treatment was not a randomized group, so we had limited power to evaluate post-treatment vaccine efficacy. Because no any sexual behavior data was collected, we were not able to evaluate the sexual behavior difference between two groups,” they observe. Zhao and colleagues advocate that further studies are needed to confirm the hypothesis whether the vaccine could prevent reactivation of latent infection and reduce spread of an existing infection by restraining the ability of the virus to infect new cells.