# Glioblastoma Immunotherapy and the Aging Immune System: What Older Patients Need to Know

This systematic review and meta-analysis examined 30 clinical trials involving 556 glioblastoma (GBM) patients to determine whether older age affects how well immunotherapy works. Researchers found that patients aged 65 and older had a significantly higher risk of dying within one year of immunotherapy treatment compared to younger patients (risk ratio 1.29, p=0.004), with the effect even stronger in newly diagnosed GBM (risk ratio 2.34, p=0.0026). The study also uncovered a troubling pattern: GBM clinical trials disproportionately enroll younger patients, with only 18% of participants aged 65 or older, despite GBM being primarily a disease of older adults (median age at diagnosis: 64). This age bias was not present in lung cancer immunotherapy trials, suggesting GBM trials may not accurately represent the patient population most affected by this disease.

# Glioblastoma Immunotherapy and the Aging Immune System: What Older Patients Need to Know

## Table of Contents

- Key Points
- Background: Why This Research Matters
- The Aging Immune System Explained
- Study Methods: How the Research Was Conducted
- Key Finding #1: Higher Risk of Death in Older Patients
- Key Finding #2: Age Matters More in Newly Diagnosed GBM
- Key Finding #3: Vaccine-Based Therapies May Be More Affected by Age
- Key Finding #4: Clinical Trials Are Skewed Toward Younger Patients
- Clinical Implications: What This Means for Patients
- Study Limitations: What This Research Couldn't Prove
- Recommendations for Patients and Researchers
- Frequently Asked Questions
- Source Information

## Key Points

- A meta-analysis of 30 trials (556 patients) found older GBM patients had a 29% higher risk of death within one year of immunotherapy.
- In newly diagnosed GBM, patients 65+ had more than double the risk of dying within one year (risk ratio 2.34).
- Vaccine-based immunotherapies showed a 38% increased risk for older patients, but the difference was not clearly stronger than non-vaccine therapies.
- Only 18% of phase II and 26% of phase III GBM immunotherapy trial participants were aged 65+, skewing results toward younger patients.
- Lung cancer immunotherapy trials had a balanced age split, but GBM trials enrolled younger patients, raising concerns about real-world applicability.

## Background: Why This Research Matters

Immunotherapy has revolutionized cancer care, offering long-term benefits that were once thought impossible for many cancer patients. These treatments work by harnessing the body's own immune system to identify and destroy cancer cells while sparing healthy tissue—something traditional treatments like chemotherapy and radiation cannot do.

However, immunotherapy has faced significant setbacks when applied to complex solid tumors like glioblastoma (GBM), the most common and aggressive form of brain cancer. GBM is notably difficult to treat because it creates a highly immunosuppressive environment, essentially "turning off" the very immune cells that immunotherapy is trying to activate.

The researchers point out a critical disconnect: despite multiple immunotherapy approaches showing promise in early-phase trials, they have repeatedly failed to demonstrate meaningful benefit in large randomized controlled trials. This pattern has resulted in tens of millions of dollars invested without therapeutic gain for patients.

Perhaps most importantly, GBM is fundamentally a disease of older adults, with a median age at diagnosis of 64 years. Yet very little research has examined how the aging immune system—which naturally weakens over time—affects a patient's ability to respond to immunotherapy. This study was designed to address that gap.

## The Aging Immune System Explained

The human immune system begins to decline around age 50, with significant thymic atrophy (shrinking of the thymus gland, where immune cells mature) taking hold by age 65. This leads to major shifts in the balance of circulating T-cells, the specialized white blood cells that coordinate the immune response.

-
**Increased senescent T-cells:** These are "retired" immune cells that no longer divide or function properly but accumulate with age.
-
**Loss of effector memory cells:** These are the cells that "remember" past infections and respond quickly to re-exposure, and their decline weakens vaccine responses.
-
**Weakened vaccine response:** The immune system's ability to generate protective immunity from vaccines declines with age—this is why the CDC recommends vaccine boosters for individuals over age 65 for flu, COVID-19, and shingles.

The researchers raise a critical question: if we know the aging immune system responds poorly to vaccines for infectious diseases, why wouldn't it also respond poorly to cancer vaccines and other immunotherapies designed to train the immune system? This study aimed to answer that question using real patient data from clinical trials.

## Study Methods: How the Research Was Conducted

The research team performed a systematic review and meta-analysis following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines—the gold standard for this type of research. They searched the PubMed and Cochrane databases for registered clinical trials conducted from January 1, 2000, through April 1, 2025.

The search included a comprehensive list of terms related to glioblastoma immunotherapy, including:

- "Glioblastoma and immunotherapy"
- "Glioblastoma and virus"
- "Glioblastoma and cellular vaccination"
- "Glioblastoma and peptide vaccination"
- "Glioblastoma and checkpoint inhibitors" (medications like PD-1 and CTLA-4 inhibitors)
- "Glioblastoma and PD-1"
- "Glioblastoma and CTLA-4"
- "Glioblastoma and cytokine therapy"
- "Glioblastoma and CAR-T" (engineered immune cells)
- "Glioblastoma and immune stimulation"
- "Glioblastoma and immune microenvironment"
- "Glioblastoma and dendritic cell vaccination"

**Inclusion criteria and age grouping:** Only phase II, III, and IV clinical trials were included. Each trial's participants were grouped into two categories: aged (65 years and older, considered the "experimental" group) and young (64 and under, considered the "control" group). The primary outcome was overall survival (OS) at one year post-treatment.

**Statistical analysis:** The pooled risk ratio (RR) of death at or before one year was calculated using both random and common effects models, with the random effects model calculated by the Mantel-Haenszel method. Heterogeneity (variability between studies) was assessed using the I² statistic, and publication bias was evaluated using contoured funnel plots. Analyses were conducted using R Version 4.4.2 with the meta package version 8.2-1. Data extraction was performed by three independent investigators and verified by a final review.

In total, **30 studies met the inclusion criteria, encompassing 556 patients**—98 patients aged 65 or older and 458 patients aged 64 or younger. A full list of the included phase II trials is shown in the table below.

**Phase II GBM Immunotherapy Trials Included in the Meta-Analysis**

Study Author (Year)
Immunotherapy Type
Primary or Recurrent
% Aged (65+) in Trial
Total N

Inoges 2017
DC Vax whole lysate
Primary
35%
31

Weathers 2020
CMV specific expanded T-cells
Mixed
5%
20

Cho 2012
DC Vax whole lysate
Primary
6%
18

Batich 2020
CMV targeted DC vax
Primary
22%
23

Lim 2021
Ex-vivo expanded/activated T and NK cells
Recurrent
7%
14

Izumoto 2008
Peptide vaccine for WT1 antigen
Recurrent
19%
21

Geletneky 2017
Oncolytic parvovirus
Recurrent
28%
18

Wheeler 2008
DC Vax whole lysate
Mixed
15%
34

Tamura 2020
Peptide vaccine to VEGF
Primary
25%
4

Fadul 2011
DC Vax whole lysate
Primary
40%
10

Migliorini 2019
Multi-peptide vaccine
Primary
31%
16

Yamanaka 2003
DC Vax whole lysate
Recurrent
29%
7

Chang 2011
DC Vax autologous
Mixed
14%
14

Todo 2022
Oncolytic herpes virus
Recurrent
21%
19

Todo 2022
Oncolytic herpes virus
Recurrent
8%
13

Schalper 2019
Neoadjuvant nivolumab
Mixed
17%
30

Vik-MO 2013
DC Vax targeted to stem cells
Primary
0%
7

Jan 2018
DC Vax autologous
Primary
7%
27

Hunn 2014
DC Vax autologous
Recurrent
14%
14

Rudnick 2020
DC Vax + Glidel wafer
Mixed
22%
23

Desjardins 2018
Poliovirus
Recurrent
13%
61

Hilf 2018
Neoantigen peptide vaccine
Primary
19%
16

Chiocca 2011
Oncolytic herpes virus
Primary
20%
10

Prins 2011
DC Vax
Mixed
13%
23

van Putten 2022
Convection-enhanced delivery of oncolytic virus
Recurrent
16%
19

Freeman 2006
Oncolytic virus
Recurrent
0%
11

Liau 2005
DC vaccine
Mixed
8%
12

Brown 2022
CAR-T with steroid resistance
Recurrent
17%
6

Smith 2020
CMV specific expanded T-cells
Primary
14%
21

Mitsuya 2020
DC Vax synthetic cocktail pulse
Primary
36%
14

## Key Finding #1: Higher Risk of Death in Older Patients

The most important finding was that **patients aged 65 and older had a significantly higher risk of death at or before one year after immunotherapy treatment** compared to younger patients. The pooled risk ratio across all 30 studies was **1.29 (95% confidence interval: 1.09–1.53, p = 0.004)**.

In plain language: older patients had a 29% higher risk of dying within one year of treatment compared to patients under 65. This result was statistically significant (p = 0.004), meaning there is less than a 0.4% chance this finding was due to random chance alone.

The researchers also checked for publication bias—the tendency for studies with positive results to be published more often than those with negative results. The I² statistic was only 10.9%, indicating very little heterogeneity (variability) between the studies and lending confidence to the pooled result.

To further strengthen their analysis, the team performed a single-patient-level analysis examining known predictors of survival in GBM: MGMT methylation status, IDH mutation status, and gender. Of the 213 patients with newly diagnosed GBM in the included studies, only 96 had complete data on all these factors. ANOVA analysis demonstrated **no significant predictive value for any of these variables on overall survival**, suggesting that age itself—not these other factors—was driving the observed differences in outcomes.

The researchers also looked at published phase III clinical trials that had calculated hazard ratios (a measure of risk over time) for age. They identified only 4 trials that had conducted this type of analysis, and while the data showed no significant effect of age on immunotherapy outcomes in these larger trials, all of these trials included disproportionately few patients over age 65—hampering any meaningful conclusions.

## Key Finding #2: Age Matters More in Newly Diagnosed GBM

Researchers hypothesized that immunotherapy would be more beneficial when given at the time of initial diagnosis rather than waiting until the tumor recurs. They separated the trial data into newly diagnosed GBM and recurrent GBM to see how age affected outcomes in each group.

The results were striking:

-
**Newly diagnosed GBM:** The risk ratio of death at or before 1 year for aged patients was **2.34 (95% CI: 1.39–3.61, p = 0.0026)**—meaning older patients had more than double the risk of dying within one year compared to younger patients.
-
**Recurrent GBM:** The risk ratio was lower but still significant at **1.23 (95% CI: 1.05–1.42, p = 0.0119)**—a 23% increased risk for older patients.

Both analyses had I² statistics below 10%, indicating very low heterogeneity and strong reliability of the findings. When the researchers compared the risk ratios and confidence intervals between the two groups, there was little overlap, confirming that the age effect was genuinely larger in newly diagnosed disease.

This finding is particularly important because many experts believe immunotherapy has the best chance of working when the tumor is first diagnosed, before it has fully established its immunosuppressive defenses. If older patients are not benefiting as much at this critical early timepoint, it suggests the aging immune system may be unable to mount the robust response that immunotherapy requires.

## Key Finding #3: Vaccine-Based Therapies May Be More Affected by Age

One well-documented effect of immune system aging is the reduced response to vaccinations. This has been extensively studied for infections like flu, COVID-19, and shingles, but rarely examined in the context of cancer vaccines.

The researchers divided the trials into two categories:

-
**Vaccine-based immunotherapies:** Including dendritic cell (DC) vaccines and peptide vaccines, which work by training the immune system to recognize and attack tumor cells.
-
**Non-vaccine-based immunotherapies:** Including checkpoint inhibitors, oncolytic viruses, CAR-T cells, and other approaches.

For **vaccine-based immunotherapies**, older patients had a significantly higher risk of death at or before 1 year: **risk ratio 1.38 (95% CI: 1.04–1.83, p = 0.0294)**—a 38% increased risk.

For **non-vaccine-based immunotherapies**, the increased risk was smaller and not statistically significant: **risk ratio 1.23 (95% CI: 0.95–1.58, p = 0.1032)**.

When the confidence intervals of the two groups were compared, they overlapped significantly, indicating the difference between vaccine and non-vaccine therapies may be weak or nonexistent with current data. The smaller sample size in the non-vaccine group did increase the I² statistic, but it remained under 30%, indicating low to no publication bias or heterogeneity.

This finding suggests that the age-related decline in vaccine response—so well documented for infectious diseases—may also apply to cancer vaccines. However, the researchers emphasize that more targeted studies are needed to fully explore this possibility.

## Key Finding #4: Clinical Trials Are Skewed Toward Younger Patients

During the literature review, the researchers noticed a troubling pattern: GBM clinical trials were enrolling younger patients than the actual GBM patient population. This matters because if trial results don't reflect the real patient population, the findings may not apply to the people who most need the treatment.

**Phase II trials:** Across the 30 studies and 556 patients, only **18% of participants were aged 65 or older**. When calculated as proportions across studies, there was a highly significant difference: **17% aged vs. 82% younger patients (p < 0.0001)**. Notably, no study included more than 40% aged individuals.

**Phase III trials:** The researchers examined 9 phase III GBM immunotherapy trials with 2,342 patients and found similar bias: only **26% of enrolled participants were over age 65** (26% vs. 73%, p < 0.0001).

**Comparison to lung cancer:** To determine whether this was a pervasive problem across oncology, the researchers applied the same analysis to lung cancer immunotherapy trials—another cancer diagnosed in older adults, with a median age at diagnosis of about 70 years. Remarkably, lung cancer trials showed nearly a **50/50 split** between patients above and below age 65, with no statistically significant difference in the proportion of older patients (more than 50% of lung cancer phase III trial participants were over 65).

**Direct comparison:** The average age of participants in phase III GBM immunotherapy trials was **57 years**, compared to **67 years** in lung cancer trials—a difference that was highly statistically significant (p < 0.0001).

The table below summarizes the phase III GBM trials examined for age bias:

**Phase III GBM Immunotherapy Trials Examined for Age Bias**

Study Author (Year)
% Aged Patients
Mean/Median Age
Total N
Age Subgroup Analysis?

Reardon 2020
23%
55
184
No

Reardon 2020
16%
55
185
No

Lassman 2025
N/A
59.5
80
No

Lassman 2025
N/A
61
79
No

Kong 2016
N/A
53
91
No

Kong 2016
N/A
53
89
No

Narita 2018
N/A
52.5
58
Yes—found age <70 was an HR increase, but <50 or 50–69 wasn't significantly different

Narita 2018
N/A
59
30
(same trial arms)

Liau 2023
22%
N/A
232
Yes—found both ages > and < 65 favored DC vax

Liau 2023
N/A
56
64
(same trial arms)

Westphal 2015
N/A
53
71
No

Westphal 2015
N/A
56
71
No

Lim 2022
32%
60
358
Yes—found age does worse in immunotherapy but only over 75; 65–75 wasn't significant

Lim 2022
34%
60
358
(same trial arms)

Weller 2017 (partial data available)
N/A
N/A
N/A
N/A

## Clinical Implications: What This Means for Patients

This study provides some of the first comprehensive evidence that **patient age may significantly impact the effectiveness of immunotherapy for glioblastoma**. For older patients considering immunotherapy, this research highlights several important points:

-
**Age matters most at diagnosis:** The effect of age was strongest in newly diagnosed GBM, where older patients had more than double the risk of death within one year. This is especially relevant since GBM is most commonly diagnosed in people in their 60s and 70s.
-
**Vaccine-based therapies may be particularly affected:** If you're considering a dendritic cell vaccine or peptide vaccine, understand that the aging immune system may not respond as robustly as a younger person's immune system would.
-
**Trial results may not apply to you:** Since GBM clinical trials have historically enrolled far fewer older patients, the published results of these trials may overestimate the benefits of immunotherapy in the real-world older GBM population.

The researchers emphasize that these findings should not necessarily discourage older patients from pursuing immunotherapy—rather, they highlight the need for more honest conversations between patients, families, and doctors about expected outcomes. They also underscore the need for clinical trials specifically designed to evaluate immunotherapy in older adults, rather than extrapolating from younger patient data.

## Study Limitations: What This Research Couldn't Prove

The researchers were transparent about the limitations of their analysis:

-
**High risk of bias in all included trials:** Using the Cochrane risk-of-bias tool, all 30 trials scored in the "high risk" category, primarily due to the lack of true randomization in their designs. This is a common limitation in phase II cancer trials.
-
**Incomplete individual patient data:** Of 213 patients with newly diagnosed GBM, only 96 had complete data on all predictive factors (MGMT methylation, IDH mutation, and gender), limiting the power of the subgroup analysis.
-
**Few phase III trials reported age breakdowns:** Only 4 phase III trials had calculated hazard ratios for age, and all included very few patients over 65, limiting meaningful conclusions from these larger studies.
-
**Review was not pre-registered:** The authors noted that this review was not pre-registered and a pre-protocol was not prepared, which some researchers view as a methodological limitation.
-
**Small subgroup sample sizes:** The non-vaccine-based immunotherapy cohort had a smaller sample size, which increased the I² statistic (though it remained below 30%, indicating acceptable levels of heterogeneity).
-
**Observational nature:** This is a meta-analysis of existing trial data, not a prospective study. It can identify associations but cannot prove that aging directly causes poorer immunotherapy outcomes.

## Recommendations for Patients and Researchers

Based on their findings, the researchers make several specific recommendations:

1.
**For researchers:** Track and report age-specific outcomes in all immunotherapy trials. The authors noted that "trial designs with better tracking and reporting of this variable will allow for a more careful examination of this effect and overall successful immunotherapy development."
1.
**For trial sponsors:** Actively recruit older patients into GBM immunotherapy trials to ensure the trial population reflects the actual disease population. The current bias toward younger patients—not seen in lung cancer trials—must be corrected.
1.
**For older GBM patients:** Ask your doctor about whether the clinical trial evidence for any proposed immunotherapy includes patients in your age group. If older patients were underrepresented in the trials, ask what that might mean for your expected outcomes.
1.
**For the research community:** Recognize that the aging immune system—with its decline in T-cell function, thymic atrophy, and weakened vaccine response—may be a fundamental biological factor in immunotherapy efficacy. This should be studied as a primary variable, not an afterthought.
1.
**For future studies:** Conduct more targeted research on vaccine-based immunotherapies in older adults, given the well-documented age-related decline in vaccine response that was reflected in this analysis.

The broader message is clear: as the U.S. population ages rapidly, and since cancer—including GBM—is fundamentally a disease of older adults, understanding how immunotherapy interacts with the aging immune system is not optional. It is essential for ensuring that the promise of immunotherapy extends to all patients who need it, regardless of age.

## Frequently Asked Questions

### Why might older adults respond worse to glioblastoma immunotherapy?

The immune system weakens with age, especially after 65. Older adults have more senescent T-cells, fewer memory cells, and a weaker response to vaccines. Since many immunotherapies train the immune system, this age-related decline may reduce their effectiveness in older glioblastoma patients.

### Are vaccine-based immunotherapies more affected by age than other types?

Possibly. For vaccine therapies like dendritic cell or peptide vaccines, older patients had a 38% higher risk of death within one year. For non-vaccine therapies, the increase was smaller and not statistically significant. However, the difference between the two may be weak.

### Are glioblastoma clinical trials representative of older patients?

No. Only 18% of participants in phase II GBM immunotherapy trials were 65 or older, and 26% in phase III trials. This is far lower than the real-world GBM population, where median age at diagnosis is 64. Results may not apply to older patients.

### Should older patients with glioblastoma avoid immunotherapy because of this study?

Not necessarily. The researchers say these findings should not discourage older patients from pursuing immunotherapy. Instead, they emphasize honest conversations with doctors about expected outcomes and the need for trials that include older adults. Your doctor can help weigh risks and benefits.

### What should I ask my doctor before starting immunotherapy for glioblastoma?

Ask whether the clinical trial evidence for the proposed immunotherapy included patients in your age group. If older patients were underrepresented, ask what that might mean for your expected outcomes. Also ask if your age could affect how well the treatment works, especially if it is a vaccine-based therapy.

### If I'm over 65 with glioblastoma, should I get a second opinion about immunotherapy?

Patients aged 65 and older with glioblastoma had a 29% higher risk of death within one year of immunotherapy than younger patients, and more than double the risk among newly diagnosed cases. Clinical trials for glioblastoma immunotherapy have enrolled very few older adults, so published results may not reflect your expected outcome. A second opinion can help you ask whether the proposed immunotherapy has evidence for patients in your age group, especially for vaccine-based therapies, which appeared more affected by age. Diagnostic Detectives Network provides independent expert second opinions.

## Source Information

**Original article title:** Glioblastoma immunotherapy in the context of the aging immune system: a systematic review and meta-analysis.

**Authors:** Shireman JM, Ammanuel S, Cheng L, Distler E, Tao Y, Kendziorski C, Dey M.

**Journal:** Journal of Neuro-Oncology (2026), Volume 176, Article 164

**DOI:** https://doi.org/10.1007/s11060-025-05395-1

**Published online:** January 12, 2026 (received November 8, 2025; accepted December 18, 2025)

**Affiliations:** Department of Neurosurgery, University of Wisconsin School of Medicine & Public Health, UW Carbone Cancer Center; and Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

This patient-friendly article is based on peer-reviewed research. The original study was funded and conducted by researchers at the University of Wisconsin, and the full text is available through the Journal of Neuro-Oncology. This translation is provided for educational purposes and does not constitute medical advice. Patients should discuss their individual treatment options with their healthcare team.


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