When you are scheduled to receive chemo and immunotherapy, delaying immunotherapy by 3-4 days after chemotherapy may help you live longer

Vikas P. Sukhatme, MD, ScD

Last updated 4/8/2025

Introduction

Over the past decade, remarkable progress has been made in cancer therapy, particularly in the use of immunotherapy for solid tumors. Yet, despite the power of immune-based treatments like PD-1 inhibitors, many patients still don’t respond as well as hoped. Recent research from both laboratory models and clinical trials has uncovered a powerful insight: the timing of when chemotherapy and immunotherapy are given could make all the difference.

Understanding the Standard Approach

For advanced non-small cell lung cancer (NSCLC) and other solid tumors, doctors often combine chemotherapy and immunotherapy as a first-line treatment. Chemotherapy helps kill cancer cells directly, while immunotherapy boosts the immune system to recognize and destroy what’s left. Traditionally, both are given on the same day. But scientists began to ask: what if giving them at different times worked better?

What the Research Discovered

Multiple clinical and laboratory studies now suggest that delaying immunotherapy by a few days after chemotherapy may lead to better results for patients.

  • In lung cancer patients (Huo et al. 2024, Liang et al. 2024, Yao et al. 2021), delaying immunotherapy in the form of PD-1 inhibitors by 3 to 5 days after chemo increased tumor shrinkage and improved survival.
  • In esophageal cancer patients (Xing et al. 2021), the delayed schedule showed a trend toward more complete tumor responses.
  • In animal and virus models (Ahmed et al. 2024, Pittet et al. 2016), delaying immunotherapy avoided damage to crucial immune cells and allowed them to recover and function more powerfully.

The Science Behind the Delay

Here's what’s happening under the microscope:

  • Right after chemotherapy, immune cells—especially the cancer-killing CD8+ T cells—are temporarily weakened or wiped out.
  • By Day 3 to Day 5, the immune system begins to rebound. That’s when CD8+ T cells start recovering, and suppressive immune cells (cells like so-called MDSCs) drop in number.
  • Giving immunotherapy during this "recovery window" boosts the immune system’s strength right when it’s primed to attack cancer.

Pre-clinical work from the Pittet et al. 2016 and Liu et al. 2010 teams showed that chemotherapy can sensitize tumors—that is, make them more recognizable to the immune system by increasing antigen visibility and promoting “immunogenic” tumor cell death. But if immunotherapy is given too early, during the immune system’s weakest phase, it may not be as effective.

Ahmed et al. 2024 confirmed this in a virus model: chemotherapy blunted the immune-boosting effects of PD-1 therapy when given at the same time, but not when PD-1 therapy was delayed.  The results were clear-cut.

The Clinical Proof

  • Huo et al. (2024) conducted a large prospective trial of 170 NSCLC patients and found that a 3-day delay led to better response rates (68% vs. 37%) and longer time before cancer progression (from 8.3 to 14.4 months).
  • Liang et al. (2024) used a low-dose chemo + delayed PD-1 combo in operable lung cancer patients and achieved major pathologic responses in nearly half the patients—indicating real tumor killing.
  • Yao et al. (2021) showed, in refractory lung cancer patients, that those who got PD-1 inhibitors 3–5 days after chemo lived longer than those who got both drugs on the same day.
  • Xing et al. (2021) found that delaying immunotherapy improved tumor response in esophageal cancer, although the sample size was small.

Across all these studies, the delayed strategy did not increase side effects—and in some cases, actually reduced them. For more details on the clinical studies given below.

These four studies, spanning both lung and esophageal cancers, make a compelling case: delaying immunotherapy by 3–5 days after chemotherapy consistently improves outcomes across various treatment settings—first-line, salvage and pre-surgery. With minimal added risk and no new drugs required, this strategy holds potential for wide, immediate clinical adoption.

What This Means for Patients

If you or a loved one is receiving chemo-immunotherapy for lung or esophageal cancer, these studies suggest a simple but powerful idea: waiting a few extra days to receive immunotherapy may help your body fight the cancer more effectively.

This does not require new drugs, just a new schedule—and early data shows it may significantly increase your chances of shrinking the tumor and/or staying cancer-free longer.

Looking Ahead: Personalized Timing

These discoveries open a new chapter in cancer care—one where not just the type of treatment, but when it is given, could change the outcome.

Doctors and researchers are exploring which cancers respond best to delayed schedules, whether low-dose chemo plus delayed immunotherapy can reduce side effects and how  blood markers like circulating tumor DNA or immune cell profiles can help fine-tune timing for each patient.

Final Thoughts

For patients whose cancers are being treated with immunotherapy, these findings offer new hope—not from a costly new drug, but from smarter scheduling of existing treatments. It may be worth asking your oncologist whether delayed immunotherapy is worth exploring in your case or available through clinical trials.  We are working hard to get a trial written and underway.

Small timing shifts may make a big difference. In cancer care, every day counts—and when given wisely, each day can count even more.

Finally, please listen to our February 2025 interview on Facebook Live sponsored by LUNGevity and to scan the accompanying slides.  There is information there (with a summary on slides 14 and 15) on additional easy to implement and affordable interventions to consider when you are on immunotherapy by itself or on chemotherapy and immunotherapy together.  And don’t forget to join our cancer registry and learn from the experience of others like you. 

References Cited

  1. Huo Y, et al. Optimal timing of anti-PD-1 antibody combined with chemotherapy administration in patients with NSCLC. J Immunother Cancer. 2024;12:e009627.
  2. Liang C, et al. Low-dose chemotherapy combined with delayed immunotherapy in the neoadjuvant treatment of non-small cell lung cancer. eLife (submitted). 2024;12:e99720.
  3. Yao W, et al. Impact of the combined timing of PD-1/PD-L1 inhibitors and chemotherapy on the outcomes in patients with refractory lung cancer. ESMO Open. 2021;6(2):100094.
  4. Xing W, et al. The sequence of chemotherapy and toripalimab might influence the efficacy of neoadjuvant chemoimmunotherapy in locally advanced esophageal squamous cell cancer. Front Immunol. 2021;12:772450.
  5. Ahmed R, et al. Platinum-based chemotherapy attenuates the effector response of CD8 T cells to concomitant PD-1 blockade. Clin Cancer Res. 2024;30(9):1833–1845.
  6. Pittet MJ, et al. Immunogenic chemotherapy sensitizes tumors to checkpoint blockade therapy. Immunity. 2016;44(2):343–354.
  7. Liu WM, et al. Pre-treatment with chemotherapy can enhance the antigenicity and immunogenicity of tumours by promoting adaptive immune responses. Br J Cancer. 2010;102(1):115–123.

 

Clinical Proof: Evidence from Patients

While laboratory experiments laid the foundation for understanding the timing of chemo-immunotherapy, clinical trials in patients and retrospective analysis of patient outcomes data have provided initial evidence that delaying immunotherapy by a few days after chemotherapy leads to significantly improved outcomes in lung and esophageal cancer.

Huo and colleagues conducted a multicenter prospective trial involving 170 patients with advanced non-small cell lung cancer (NSCLC). These patients were divided into two groups:

  • Simultaneous group (n = 102): Received anti-PD-1 therapy on the same day as platinum-based chemotherapy.
  • Delayed group (n = 68): Received the same anti-PD-1 therapy three days after chemotherapy.

The results were striking:

  • Objective Response Rate (ORR): 68% in the delayed group vs. 37% in the simultaneous group.
  • Disease Control Rate (DCR): 98% vs. 81%.
  • Progression-Free Survival (PFS): Significantly longer (14.4 months) in the delayed group  vs 8.3 months in the simultaneous group.
  • The benefits were confirmed through flow cytometry and RNA sequencing of blood samples, which showed improved recovery of CD8+ T cells, expansion of new T cell receptor clones, and increased anti-tumor immune activity in the delayed group.

This trial provided one of the first high-quality clinical datasets proving that altering treatment timing—not drugs—could significantly improve efficacy in lung cancer without additional side effects.

Liang and colleagues tested a modified neoadjuvant (pre-surgery) treatment regimen in 38 patients with resectable stage IIA–IIIA NSCLC. The regimen included:

  • Low-dose platinum-based chemotherapy on Day 1, followed by
  • Delayed immunotherapy (PD-1 inhibitor) on Day 5.

This trial uniquely combined slightly reduced chemotherapy dosing with delayed immune activation, aiming to maintain efficacy while minimizing toxicity.

Key outcomes:

  • Objective Response Rate (ORR): 73.7%.
  • Major Pathological Response (MPR): 47.4%—meaning less than 10% of tumor tissue remained after treatment.
  • Pathological Complete Response (pCR): 31.6%—indicating complete disappearance of all cancer cells before surgery.
  • Importantly, only one patient experienced a Grade 3 adverse event, showing the regimen’s excellent tolerability.

They also tracked circulating tumor DNA (ctDNA) and T cell receptor (TCR) diversity in blood samples. After the first cycle of chemotherapy, patients demonstrated decreased tumor burden and increased expansion of tumor-reactive T cells, especially after the delayed immunotherapy. These findings offer strong biological support for the benefit of delayed administration.

Yao and colleagues performed a retrospective analysis of 64 patients with advanced or refractory lung cancer who had already received multiple lines of treatment. They were divided based on when they received PD-1/PD-L1 inhibitors in relation to chemotherapy:

  • Group A (delayed): Immunotherapy given 1–10 days after chemotherapy, with a subgroup focus on 3–5 day delays.
  • Group B (simultaneous or prior): Received immunotherapy before or concurrently with chemotherapy.

The study revealed:

  • Overall Survival (OS): 17.3 months for the delayed group vs. 12.7 months in the simultaneous group.
    • In multivariate analysis (controlling for other clinical variables), delayed timing had a hazard ratio of 0.36, indicating a 64% reduction in risk of death (p = 0.012).
  • Progression-Free Survival (PFS): Trend towards improvement in the delayed group (5.1 vs. 4.2 months), though not statistically significant in this smaller cohort.
  • In vitro studies accompanying the clinical data showed that administering PD-1 inhibitors three days after chemotherapy reduced cytotoxic damage to lymphocytes, allowing T cells to survive and function better.

These findings were especially significant because the patients were heavily pretreated, demonstrating that even in later stages of disease, timing can re-sensitize the immune system and improve outcomes.

This randomized Phase II study evaluated 30 patients with locally advanced esophageal squamous cell carcinoma (ESCC). Patients were assigned to:

  • Experimental group: Chemotherapy (paclitaxel and cisplatin) on Day 1, followed by toripalimab (PD-1 inhibitor) on Day 3.
  • Control group: Received both chemotherapy and toripalimab on Day 1 (simultaneous administration).

Following two cycles of treatment:

  • Pathologic Complete Response (pCR):
    • 36% in the delayed group vs. 7% in the simultaneous group.
    • Though not statistically significant (p = 0.079) due to small sample size, the difference was clinically meaningful and trend-favoring.
  • Safety profile: Similar between both groups, with manageable adverse events.

This was one of the first randomized studies to examine the timing of PD-1 inhibitors in the curative-intent neoadjuvant setting for esophageal cancer—suggesting the benefits of delay extend beyond NSCLC.