A phase 1b clinical trial optimizing regulatory T cell depletion in combination with platinum-based chemotherapy in thoracic cancers

Our plain-English summary of A phase 1b clinical trial optimizing regulatory T cell depletion in combination with platinum-based chemotherapy in thoracic cancers, by A.M. Cook, A. McDonnell, M.J. Millward, et al (Expert Review of Anticancer Therapy, 2021).

The study

• Authors: A.M. Cook, A. McDonnell, M.J. Millward, J. Creaney, A. Hasani, M. McMullen, T. Meniawy, B.W.S. Robinson, R.A. Lake, A.K. Nowak
• Journal: Expert Review of Anticancer Therapy
• Published: 2021;21(5):465-474
• Cited by: 2 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: Single-agent cyclophosphamide can deplete regulatory T-cells (Treg). We aimed to determine optimal dosing and scheduling of oral cyclophosphamide, alongside pemetrexed-based chemotherapy, to deplete Treg in mesothelioma or non-small-cell lung cancer patients.Methods: 31 Patients received pemetrexed ± cisplatin or carboplatin on day 1 of a 21-day cycle (maximum 6 cycles). From cycle two, patients received cyclophosphamide, 50 mg/day, with intrapatient escalation to maximum 100/150 mg/day alternately. Immunological changes were examined by flow cytometry. Primary endpoint was Treg proportion of CD4+ T-cells, with doses tailored to target Treg nadir <4%.Results: Reduction in Treg proportion was observed on day 8 of all cycles, and was not augmented by cyclophosphamide. Few patients achieved the <4% Treg target. Treg proliferation reached nadir one week after chemotherapy, and peaked on day 1 of the subsequent cycle. Efficacy parameters were similar to chemotherapy alone. Seventeen percent of patients ceased cyclophosphamide due to toxicity.Conclusions: Specific Treg depletion to the degree seen with single-agent cyclophosphamide was not observed during pemetrexed-based chemotherapy. This study highlights the poor evidence basis for use of cyclophosphamide as an immunotherapeutic in combination with chemotherapy, and the importance of detailed flow cytometry studies.Trial registration: Clinical trial registration: www.anzctr.org.au identifier is ACTRN12609000260224.

In plain English

This early-phase (phase Ib) trial took place at one hospital in Western Australia. Between June 2009 and June 2012, 34 patients were enrolled. Results cover 31 eligible patients: 27 with malignant pleural mesothelioma and 4 with non-small cell lung cancer. All received pemetrexed, alone or with cisplatin or carboplatin. From the second cycle, 29 also took low-dose oral cyclophosphamide; two left before receiving any. Doses were to be adjusted per patient, aiming to lower regulatory T cells (immune-suppressing cells) to 4% or less of CD4+ T cells. In blood samples, the proportion of these cells showed no lasting drop during cyclophosphamide treatment, and did not differ significantly between chemotherapy alone and chemotherapy plus cyclophosphamide. Of 30 patients assessed, 11 (37%) had a partial response. Median overall survival was 17.4 months (95% confidence interval 14.1 to 23.1 months). Grade 3 anemia affected 48% of patients; 17% stopped cyclophosphamide due to toxicity. The authors concluded the combination was tolerable, with efficacy similar to that expected from chemotherapy alone, but did not deplete regulatory T cells to the degree seen with cyclophosphamide alone. They noted the mixed patient group as a limitation.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Prospective, single-center, phase Ib clinical trial with dose escalation within each patient
• Who was studied: 34 patients enrolled from June 2009 to June 2012 at Sir Charles Gairdner Hospital, Western Australia. 31 were eligible and analysed: 27 with malignant pleural mesothelioma and 4 with stage IV non-small cell lung cancer.
• Exposure: Not an asbestos exposure study. The exposure studied was treatment: pemetrexed-based chemotherapy (pemetrexed alone, or with cisplatin or carboplatin) on day 1 of 21-day cycles, up to six cycles. From cycle 2, patients also received oral cyclophosphamide starting at 50 mg/day. The dose was to be escalated within each patient, up to alternating 100 and 150 mg/day, until a regulatory T cell nadir of 4% or less was reached. Cohort 1 took it intermittently (days 1 to 14) and cohort 2 continuously. 29 of the 31 patients actually received cyclophosphamide.
• Main results:
  • 29 of 31 patients received cyclophosphamide with chemotherapy from cycle 2. Two patients left the study before receiving any cyclophosphamide.
  • There was no lasting reduction in the regulatory T cell proportion in peripheral blood over the course of cyclophosphamide treatment.
  • There was no significant difference in regulatory T cell proportion between chemotherapy alone (cycle 1) and chemotherapy plus cyclophosphamide (cycles 2 to 6).
  • The lowest regulatory T cell proportion occurred during cycle 2 (the first cycle with cyclophosphamide) in 14 of 31 patients, and during cycle 1 (before any cyclophosphamide) in 7 of 31.
  • Best tumor response among the 30 patients evaluated: 11 (37%) had a partial response, 15 (50%) had stable disease, and 4 (13%) had progressive disease at first assessment.
  • For all 31 patients, median overall survival was 17.4 months (95% CI 14.1 to 23.1) and median progression-free survival was 6.6 months (95% CI 5.8 to 9.4).
  • Patients with epithelioid malignant pleural mesothelioma (n = 20) had significantly longer overall survival than the group with non-epithelioid mesothelioma plus non-small cell lung cancer (n = 11): 20.1 vs 8.7 months, p = 0.0085. Progression-free survival did not differ significantly: 7.7 vs 6.3 months, p = 0.097.
  • 48% of patients had grade 3 anemia. 32% had grade 3 or 4 neutropenia, but there was no febrile neutropenia while patients were receiving cyclophosphamide.
  • Seventeen percent of patients stopped cyclophosphamide because of toxicity. The five patients who stopped it but continued chemotherapy did so because of hematological toxicity (3), grade 3 fatigue (1), and grade 2 nausea or patient wishes (1).
• The authors' conclusion: The authors concluded that pemetrexed-based chemotherapy with oral low-dose cyclophosphamide was tolerable, with efficacy similar to that expected from chemotherapy alone. However, it did not deplete regulatory T cells to the degree seen with cyclophosphamide given alone, and such combinations are unlikely to enhance efficacy through regulatory T cell depletion.
• Limitations the authors state:
  • The patients were a mixed group in terms of cancer type and line of treatment.
  • Immune cells were measured in blood, not in tumor or lymph nodes.
  • There was no control arm of patients who did not receive cyclophosphamide.
  • The survival results may reflect patient selection and restrictive inclusion criteria, and cannot be confidently attributed to the treatment.
  • The subgroup survival comparison rests on small numbers.
  • Data on other immune cell types were not available.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer.

Medical terms in this study, explained in our Lexicon: Clinical Trial, Chemotherapy, Pemetrexed (Alimta), Mesothelioma, Lung Cancer, Cisplatin, Carboplatin.

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• The efficacy of the frontline platinum-based combination chemotherapy in malignant peritoneal mesothelioma — S.T. Kim, J.Y. Park, et al. (2010)
• A Phase II Trial of First-Line Combination Chemotherapy With Cisplatin, Pemetrexed, and Nivolumab for Unresectable Malignant Pleural Mesothelioma: A Study Protocol — N. Fujimoto, K. Aoe, et al. (2018)
• Correlation between TS, MTHFR, and ERCC1 gene polymorphisms and the efficacy of platinum in combination with pemetrexed first-line chemotherapy in mesothelioma patients — T. Powrózek, D.M. Kowalski, et al. (2014)
• Phase 2 study of sorafenib in malignant mesothelioma previously treated with platinum-containing chemotherapy — S. Papa, S. Popat, et al. (2013)

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