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Adenovirus-Neutralizing and Infection-Promoting Activities Measured in Serum of Human Brain Cancer Patients Treated
Ida H van der Meulen-Muileman1, Joana Amado-Azevedo1, Martine L M Lamfers2
1Amsterdam UMC location Vrije Universiteit Amsterdam, Medical Oncology, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
Abstract:
Oncolytic adenoviruses derived from human serotype 5 (Ad5) are being developed to treat cancer. Treatment efficacy could be affected by pre-existing or induced neutralizing antibodies (NAbs), in particular in repeat administration strategies. Several oncolytic adenoviruses that are currently in clinical development have modified fiber proteins to increase their infectivity. One example is Ad5-∆24.RGD, which carries a cyclic RGD peptide insert in the fiber protein to allow cell entry via integrins. The effect of anti-Ad5 NAbs on anticancer efficacy could be different for oncolytic adenoviruses with RGD-modified fibers than for unmodified Ad5-based viruses. Here, we determine pre-existing and elicited NAb titers in the serum of patients with glioblastoma who were treated by delivering Ad5-∆24.RGD to the tumor and to the surrounding tumor-infiltrated brain. We show that intracranial infusion of Ad5-∆24.RGD induced mainly neutralization of adenovirus native tropism. Infection of cells with RGD-modified virus was significantly less affected. In cerebrospinal fluid, neutralizing activity against RGD-mediated infection remained very low. Thus, the RGD-mediated alternative cell entry route allowed to bypass pre-existing and induced anti-Ad5 neutralization. Interestingly, in the course of these experiments, we discovered that the serum of most humans promotes the uptake of RGD-modified adenovirus in human cells. The until now unidentified infection-stimulating factor seems distinct from serum proteins known to promote Ad5 infection. Together, our work supports the utility of RGD-modified oncolytic adenoviruses for the treatment of cancer in humans. Since these viruses hardly induced neutralization, they seem particularly suitable for repeat administration treatments.
Insights
RGD-modified oncolytic adenoviruses bypass neutralizing antibodies in cancer patients, enabling effective repeat treatments. A novel factor in human serum enhances RGD-modified adenovirus uptake, supporting their use in cancer therapy.
Area of Science:
- Oncology
- Virology
- Immunology
Background:
- Oncolytic adenoviruses, particularly those based on human adenovirus serotype 5 (Ad5), are promising cancer therapeutics.
- Neutralizing antibodies (NAbs) against Ad5 can limit treatment efficacy, especially with repeated administrations.
- Modified adenoviruses with altered fiber proteins, like Ad5-∆24.RGD, aim to overcome NAb limitations by utilizing alternative cell entry pathways.
Purpose of the Study:
- To evaluate the impact of pre-existing and induced neutralizing antibodies (NAbs) against Ad5 on the efficacy of Ad5-∆24.RGD in glioblastoma patients.
- To determine if the RGD-modified fiber of Ad5-∆24.RGD allows for effective viral entry and infection despite anti-Ad5 NAbs.
- To investigate the presence of factors in human serum that might influence the infectivity of RGD-modified adenoviruses.
Main Methods:
- Measurement of pre-existing and elicited NAb titers in serum and cerebrospinal fluid of glioblastoma patients treated with Ad5-∆24.RGD.
- Assessment of Ad5-∆24.RGD infectivity in the presence of anti-Ad5 NAbs, comparing native tropism neutralization with RGD-mediated infection.
- Investigation of serum-mediated enhancement of RGD-modified adenovirus uptake in human cells.
Main Results:
- Intracranial delivery of Ad5-∆24.RGD primarily neutralized the virus's native tropism, with RGD-mediated infection being significantly less affected by NAbs.
- Neutralizing activity against RGD-mediated infection remained low in cerebrospinal fluid.
- A previously unidentified factor in most human sera was found to promote RGD-modified adenovirus uptake, distinct from known Ad5-enhancing factors.
Conclusions:
- RGD-modified oncolytic adenoviruses like Ad5-∆24.RGD can effectively bypass pre-existing and induced anti-Ad5 neutralizing antibodies.
- The RGD-mediated entry pathway offers a viable strategy to overcome NAb-mediated resistance in adenovirus cancer therapy.
- The discovery of an infection-stimulating factor in human serum further supports the potential of RGD-modified adenoviruses, particularly for repeat administration strategies in cancer treatment.
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