Enhancing T-cell response with monoclonal antibodies and chemotherapy in advanced gastric cancer

Abstract

This article provides a critical analysis of a prospective single arm study by Zheng et al, which assessed the impact of oxaliplatin and trastuzumab, administered every 3 weeks, for a total of six cycles in 60 patients with human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer. The study specifically explored how this treatment regimen influenced serum tumor markers and T lymphocyte subsets. After six cycles of treatment, the levels of the tumor markers carcinoembryonic antigen, carbohydrate antigen 19-9 and carbohydrate antigen 72-4 in the blood significantly dropped compared to their initial values (P < 0.001). There was a notable increase in the percentages of CD3+ and CD4+ T cells (P < 0.05), while the percentage of CD8+ T cells decreased (P < 0.05). As a result, the CD4+/CD8+ ratio also rose significantly after treatment (P < 0.05). Patients who had a reduction of 50% or more in their tumor markers and an increase of 1.5 times or more in the CD4+/CD8+ ratio showed better clinical improvements (P < 0.05). In this editorial, we will discuss these findings and how they apply to the current treatment field for advanced HER2 positive gastric cancer.

Key Words: Gastric cancer; Oxaliplatin; Trastuzumab; CD4; CD8

Core Tip: After six cycles of treatment with chemotherapy and trastuzumab it was observed that the levels of tumor markers in the blood significantly dropped compared to their initial values. Furthermore, there was a notable increase in the percentages of CD3+ and CD4+ T cells, with the CD4+/CD8+ ratio also increasing after treatment. Patients who had a reduction of 50% or more in their tumor markers and an increase in the CD4+/CD8+ ratio showed better disease outcomes. These findings can be related to the current field of advancements in the treatment of human epidermal growth factor receptor 2 positive gastric cancer, with the combination of immune checkpoint inhibitors.

TO THE EDITOR

The management of advanced gastric cancer (AGC) remains a significant challenge due to its poor prognosis, typically requiring aggressive systemic therapy, such as the standard combination of fluoropyrimidine and platinum-based chemotherapy. The overexpression of human epidermal growth factor receptor 2 (HER2), especially in the intestinal subtype, has led to advances such as the use of trastuzumab, a HER2-targeted monoclonal antibody, which significantly improves overall response rates (RR) and overall survival (OS), as shown in the TOGA trial[1,2]. Furthermore, more recently, remarkable improvements have been seen in the KEYNOTE-811 study[3], where adding pembrolizumab to trastuzumab and chemotherapy showed increased RR, and improvements in progression-free survival (PFS) and OS, particularly in patients co-expressing HER2 and programmed death ligand-1 (PD-L1) (combined positive score ≥ 1) by immunohistochemistry[3].

However, as we know, these intensified therapies can be related to increased toxicity. In the TOGA trial, about two thirds of the patients experienced grade 3 or 4 adverse events, while in the KEYNOTE-811 study, about half developed grade 3–5 adverse events. This underscores the critical need to balance efficacy with quality of life and safety, particularly in palliative care settings[2,3]. The combination of oxaliplatin and trastuzumab has been supported by several phase II and III trials in the treatment of AGC, leading to longer PFS, and improved OS rates[4,5]. Most trials evaluated oxaliplatin associated with fluoropyrimidines.

IMMUNE SYSTEM

The immune system, specifically T lymphocytes, plays a crucial role in cancer progression and treatment. CD4+ helper T cells assist CD8+ cytotoxic T cells in directly targeting tumor cells. The CD4+/CD8+ ratio, which reflects immune status, is associated with better prognosis and treatment responses in various cancers, including gastroesophageal cancers[6-8]. Additionally, serum tumor markers such as carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 19-9 and CA72-4, have emerged as promising predictive biomarkers, reflecting tumor burden and activity[6].

These markers together could be useful for personalizing treatment strategies by helping predict therapeutic responses more accurately. In this setting, the study by Zheng and colleagues evaluated the impact of systemic treatment with trastuzumab and oxaliplatin on immune system and tumor biomarkers, as predictors of response.

STUDY DISCUSSION

The study investigated the potential of combining oxaliplatin and trastuzumab as an option in de-escalating treatment for HER2-positive metastatic gastric cancer[1]. It is important to note that in the current randomized phase 3 trials evaluating first-line treatment for AGC, for example the CHECKMATE-649, TOGA trial, KEYNOTE-811 and KEYNOTE-985, all of these studies are assessing platinum-fluoropyrimidine regimens associated with monoclonal antibodies[2,3,9,10]. The impact of fluoropyrimidines in the first-line regimen is well established by randomized data, and the absence of this is an important limitation to note from the findings[1].

RESULTS

In the study, the evaluated therapy significantly reduced serum tumor markers (CEA, CA19-9, and CA72-4) and affected T lymphocyte subsets, demonstrating its antitumor activity. The study’s main hypothesis is that the drop in the investigated tumor markers could serve as an early sign of treatment response, while the increase in CD3+ and CD4+ T cells, alongside a higher CD4+/CD8+ ratio, suggests an enhanced immune response, potentially contributing to the therapy's long-term success.

The study further showed that patients with greater reductions in tumor markers and higher CD4+/CD8+ ratios achieved better clinical outcomes, indicating the potential of these biomarkers to predict treatment efficacy (higher RR) and guide therapy decisions (Table 1). These results are very important considering that activating the immune system of the patient could potentially be a predictive or prognostic biomarker of response to this treatment. After a median follow-up time of 18 months, the median PFS and OS were 8.5 months (95%CI: 6.8-10.2 months) and 16.0 months (95%CI: 13.5-18.5 months), respectively.

Table 1 Main results on response rate.

Marker/biomarker	Baseline values	After treatment	Clinical response rate (CR + PR)	P value
CEA
	15.2 (1.5-180.5)	6.1 (0.5-55.0)		< 0.001
		≥ 50% reduction	70.0% (CR + PR)	< 0.05
		< 50% reduction	40.0% (CR + PR)	< 0.05
CA19-9
	60.5 (10.5-1000.0)	26.4 (5.0-400.0)		< 0.001
		≥ 50% reduction	75.0% (CR + PR)	< 0.05
		< 50% reduction	42.9% (CR + PR)	< 0.05
CA72-4 (U/mL)
	8.0 (1.5-300.0)	2.8 (0.5-80.0)		< 0.001
		≥ 50% reduction	72.2% (CR + PR)	< 0.05
		< 50% reduction	38.5% (CR + PR)
CD3+ (%)
	62.5 (45.0-75.0)	70.0 (50.0-85.0)		< 0.05
CD4+ (%)
	30.0 (20.0-45.0)	40.0 (25.0-55.0)		< 0.05
CD8+ (%)
	28.5 (15.0-40.0)	22.0 (10.0-35.0)		< 0.05
CD4+/CD8+ ratio
	1.2 (0.6-2.5)	1.8 (0.8-3.5)		< 0.05
CD4 + /CD8 + ratio
		≥ 1.5-fold increase	71.4% (CR + PR)	< 0.05
		< 1.5-fold increase	41.7% (CR + PR)

CR: Complete response; PR: Partial response.

The biomarkers were also related to clinical response. Among the 60 patients, 5 (8%) achieved complete response, 28 (47%) achieved partial response, 20 (33%) achieved stable disease, and 7 (12%) had disease progression. Complete response and partial response were observed in 70% of patients that had a CEA reduction of more than 50% (P < 0.05), in 75% of patients that had a CA.19-9 reduction of more than 50% (P < 0.05), in 72.2% of patients that had a CA.72-4 reduction of more than 50% (P < 0.05) and in 71.4% of patients that had a CD4+/CD8+ ratio ≥ 1.5 fold increase (P < 0.05) (Table 1). CEA, CA 19-9 and CA 72-4 are routinely used for follow-up in patients treated for AGCs and the findings are aligned with the expected response for patients with clinical response to treatments.

Given that the current standard of care for HER2-positive metastatic gastric cancer typically would be a platinum-fluoropyrimidine regimen associated with trastuzumab and pembrolizumab (if PD-L1 > 1), the findings should be evaluated with caution, since most patients will receive immunotherapy that could potentially already activate and affect the immune system and tumor microenvironment. It is important to note that the positive impact of immune checkpoints inhibitors in this setting was already confirmed with the outstanding results observed on the KEYNOTE-811 trial, a randomized phase 3 trial that evaluated platinum-based chemotherapy plus pembrolizumab and trastuzumab as upfront treatment for AGC in patients with HER2 and PD-L1 amplified cancers[3].

DISCUSSION

The regimen investigated in the study, oxaliplatin combined with trastuzumab, which was administered every 21 days, could offer significant improvements in patient quality of life in a palliative care setting, considering the regimen and favorable schedule. Patients evaluated in the trial were those in a real world setting, mainly aged 50-60 years old, with metastases to the liver and or peritoneum, and HER2 was amplified by immunohistochemistry in 80% of cases, and 20% of patients were HER2 positive by fluorescence in situ hybridization testing.

Some of the study's limitations, such as its single-arm design and small sample size of 60 patients must be considered. Small sample sizes could be affected by selection bias and be more susceptible to confounding factors. While the combination of oxaliplatin and trastuzumab showed promising results, it is important to note that grade 3 adverse events occurred in 98% of patients, suggesting that even with fewer drugs, the regimen does not necessarily result in reduced toxicity. The management of toxicities in this trial was not discussed; however, considering that neutropenia was one of the most common adverse events observed (35%), it is possible that colony-stimulation factors were necessary in some cases, increasing the cost of the treatment.

Furthermore, challenges in measuring biomarkers and lymphocytes through immunophenotyping tests in resource-limited settings must be considered. The analysis of these biomarkers could be expensive in the setting of limited resources. Furthermore, absence of the evaluation of lymphocytes and other immune cells in the tumor microenvironment could also be a limitation in this study. It has been observed that the expression of CD4+ T cells and PD-L1 in the tumor microenvironment was potentially related to immune response and tumor outcomes, and these markers were not evaluated in this study. Furthermore, molecular signatures of higher immune response were also not evaluated including DNA polymerase epsilon catalytic subunit, catalytic and proofreading subunit of DNA polymerase-delta, Epstein-Barr virus, microsatellite instability high and tumor mutational burden high.

The median PFS and OS of the study[1] [8.5 months (95%CI: 6.8-10.2 months)] and 16.0 months (95%CI: 13.5-18.5 months), respectively are aligned with the findings from the TOGA trial[2] [PFS was 6.7 months (95%CI: 6-8 months)] and OS was 13.8 months (95%CI: 12-16 months) and seems to be inferior to the KEYNOTE-811 trial [PFS was 10.8 months (95%CI: 8.5-12.5 months)] and OS was 20.5 months (95%CI: 18.2-24.3 months)[3]. However, to confirm these findings, due to the small sample size (60 patients) larger randomized controlled trials are essential to compare this combination therapy against established treatments such as those in the TOGA trial and KEYNOTE-811 study[2,3]. Furthermore, longer follow-up is also necessary to assess the effect of this treatment regimen on long-term survival and quality of life.

The current standard of care for advanced gastric or gastroesophageal HER2 amplified adenocarcinomas is immune checkpoint inhibitors plus trastuzumab-platinum based chemotherapy, based on KEYNOTE-811[3]. While a three-week regimen is potentially more feasible for patients, the high rate of grade 3 adverse events combined with the absence of the anti-PD-1 is an important limitation in the interpretation of these findings. In order for this regimen to be acceptable as a potential standard of care, studies are necessary to compare different schedules and combinations, and evaluate toxicity, biomarkers and outcomes.

CONCLUSION

The study by Zheng et al[1] presents promising data on the combination of oxaliplatin and trastuzumab as a potential de-escalating treatment for HER2-positive AGC. Significant reductions in serum tumor markers and shifts in T lymphocyte subsets indicate the regimen’s antitumor activity and potential to enhance immune response, which may improve long-term outcomes. However, despite the possibility of reducing clinic visits and improving quality of life in palliative settings, the study's small sample size, single-arm design, and high rate of grade 3 adverse events, limits the generalizability of these findings. Larger randomized controlled trials with longer follow-up are essential to further validate the efficacy and safety of this combination therapy, particularly in comparison to standard treatments such as those explored in the TOGA and KEYNOTE-811 studies. Moreover, practical challenges in biomarker measurement in resource-limited settings and evaluation of the impact of the treatment in the tumor microenvironment should be addressed in future studies.