June 14, 2024

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Sequential Therapy May Outperform Current Immuno-Chemo Combination in Cancer Treatment

Sequential Therapy May Outperform Current Immuno-Chemo Combination in Cancer Treatment

Sequential Therapy May Outperform Current Immuno-Chemo Combination in Cancer Treatment

In the realm of cancer treatment, has the current approach of combining immunotherapy and chemotherapy missed the mark? Recent research suggests that a sequence of chemotherapy followed by immunotherapy might be a superior solution.

The combination of PD-1/L1 inhibitors with various chemotherapy drugs in immunotherapy regimens has been rapidly gaining ground in the frontline treatment of numerous advanced solid tumors in recent years.

The question arises: how many first-line treatments for these tumors now favor the combination of immunotherapy and chemotherapy?

The pace of advancements in this field seems almost immeasurable.

Sequential Therapy May Outperform Current Immuno-Chemo Combination in Cancer Treatment

Currently, the common practice in combining immunotherapy and chemotherapy involves simultaneous administration, known as “synchronous treatment.” However, is this approach truly optimal? A recent study published in the Clinical Cancer Research journal by a research team from Emory University School of Medicine challenges the current drug administration protocols in immunotherapy combined with chemotherapy.

The research reveals that when PD-1 inhibitors are used concurrently with chemotherapy, the chemotherapy affects the transformation of CD8+ T cells from stem-like to transitory effector cells after activation. This limits the proliferation of T cells and the production of IFN-γ, resulting in a less effective outcome compared to the use of PD-L1 inhibitors alone. On the other hand, sequential administration with chemotherapy followed by immunotherapy preserves the ability of PD-L1 inhibitors to activate the immune response, suggesting it might be a more optimal treatment strategy.

The advantage of combining immunotherapy with chemotherapy lies in the fact that chemotherapy not only effectively kills cancer cells but also enhances the release and presentation of tumor antigens in various ways. Some chemotherapy drugs also directly modulate the immune system, such as the previously mentioned pembrolizumab. These mechanisms enable chemotherapy to synergistically enhance the efficacy of immunotherapy. However, the impact of chemotherapy on the proliferation and differentiation of the main force in anticancer immunity, CD8+ T cells, during combination therapy is not fully understood.

In this study, the research team at Emory University School of Medicine used a classic mouse model of T cell exhaustion constructed from chronic infection with the lymphocytic choriomeningitis virus (LCMV). The methods used in mice, including chemotherapy, immunotherapy, or the combination of both, closely resembled the drug administration patterns in first-line treatment for advanced non-small cell lung cancer (NSCLC). This comprehensive simulation of immunotherapy combined with chemotherapy allowed for an analysis of its effects on CD8+ T cells in the mouse model.

After five treatment cycles of single-drug therapy, combination therapy, or no treatment, the researchers first analyzed the mouse spleens. They found that PD-L1 inhibitors alone led to a twofold increase in the number of CD8+ T cells specific to LCMV. However, in mice treated with combination therapy, the number of these cells in the spleen was significantly reduced (decreased by 2.2 times, P<0.001). Similar findings were observed in the analysis of T cells in the lungs, indicating that combining chemotherapy with immunotherapy on the foundation of immunotherapy diminishes the activation of T cells.

Through Ki-67 staining, the researchers observed that PD-L1 inhibitors as a monotherapy increased the proliferative CD8+ T cells (Ki-67 positive) in the spleen fourfold compared to the untreated control group, accounting for 15% of the total cells. In contrast, the combination therapy group showed no significant increase in Ki-67+CD8+ T cells, leading to a natural reduction in LCMV-specific CD8+ T cells.

In another part of the experiment conducted simultaneously, the researchers confirmed that chemotherapy significantly reduced the number of proliferative CD8+ T cells due to its cytotoxicity. Specifically, during the acute infection period of the LCMV virus, when CD8+ T cells came into contact with the virus antigen, were activated, and were about to proliferate, chemotherapy forcefully suppressed the proliferation of these T cells. This resulted in a significant decrease in both proliferative CD8+ T cells and the total number of CD8+ T cells.

In terms of the extent of the impact on proliferation, the CD8+ T cell subset most affected by chemotherapy was the transitory effector cells (characterized by PD-1+CD101-Tim3+). In mice treated with PD-L1 inhibitors alone, the Ki-67 positivity rate of these cells reached 42%. However, in the combination therapy group, it was only 26.7%. Simultaneously, the ability of transitory effector CD8+ T cells to produce IFN-γ also significantly decreased, preventing effective suppression of LCMV infection in mice.

From the perspective of differentiation ability, the CD8+ T cell subset most affected was first the stem-like subset (characterized by PD-1+TCF-1+Tim-3-). Chemotherapy did not significantly reduce the number of these cells, but when used in combination with immunotherapy, chemotherapy noticeably restricted the expansion of these CD8+ T cells and their differentiation into transitory effector cells. Another affected subset was the terminally exhausted CD8+ T cells. PD-L1 inhibitors alone effectively activated this subset of T cells, but when combined with chemotherapy, the activating effect was diminished.

Observing the various adverse effects brought about by simultaneous immunotherapy and chemotherapy, the researchers finally evaluated the sequential model of chemotherapy followed by immunotherapy. The sequential model indeed corrected various detrimental effects of synchronous combination therapy, significantly increasing the number of LCMV-specific CD8+ T cells and transitory effector CD8+ T cells. The CD8+ T cells capable of producing IFN-γ reached 5.3 times that of the synchronous therapy group, providing better control of LCMV infection.

While this is only a preliminary concept-confirming study, the researchers point out in the paper that the observed adverse effects of chemotherapy are likely not limited to the platinum-based chemotherapy regimen used in the experiments or to NSCLC as the specific type of solid tumor. Therefore, future research should promptly conduct translational studies to evaluate the adverse effects of chemotherapy when combined with immunotherapy and find the optimal drug administration strategy for combination therapy, making neoadjuvant/adjuvant therapy for NSCLC a promising experimental field.

Sequential Therapy May Outperform Current Immuno-Chemo Combination in Cancer Treatment


Mariniello A, Nasti T H, Chang D Y, et al. Platinum-based chemotherapy attenuates the effector response of CD8 T cells to concomitant PD-1 blockade[J]. Clinical Cancer Research, 2023.

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