In Situ Immunization Using Nanoparticles

In situ immunization holds promise as a way to induce a long-term, anti-lymphoma immune response that results in clinical benefit for patients.

This project in the University of Iowa/Mayo Clinic Lymphoma SPORE is designed to explore a novel approach to in situ immunization that if successful could represent a novel approach to therapy for lymphoma and other cancers.

Immunotherapy of lymphoma through in situ manipulation of an involved lymph node can allow for the development of an active anti-lymphoma immune response without the need for ex vivo handling or immunization with a specific antigen.

A comprehensive and successful approach to in situ immunization in lymphoma would require the effective presentation of antigen by the lymphoma cells or professional antigen-presenting cells, the activation of lymphoma-specific T cells, and the suppression of the regulatory arm of the immune response to enhance the development of a sustained anti-lymphoma T-cell response.

Hypothesis

The overall hypothesis of the In Situ Immunization Using Nanoparticles research project is that in situ immunization with nanoparticles will allow for the induction and maintenance of a robust anti-lymphoma immune response with acceptable toxicity.

To test this hypothesis, this Lymphoma SPORE project is assessing the effect of intratumoral injection of nanoparticles (NPs) containing doxorubicin on lymphoma cells, the immune microenvironment, and the anti-lymphoma immune response in animal models and in a phase I clinical trial in patients with lymphoma.

The in situ immunization project is also assessing the effect of intratumoral injection of nanoparticles containing both doxorubicin and the toll-like receptor 9 (TLR9) agonist CpG ODN (CpG dox NPs) in mice and people.

Finally, the project is assessing how agents capable of maintaining the T-cell response impact the success of in situ immunization with nanoparticles.

Project aims

This project has three main aims.

Aim 1: Assess the effect of in situ injection of nanoparticles containing doxorubicin on lymphoma cells

  • Aim 1a. Refine the structure of doxorubicin nanoparticles to optimize the concentration and release of doxorubicin
  • Aim 1b. Assess the toxicity, anti-tumor activity and immune effects of doxorubicin nanoparticles in mouse models of lymphoma
  • Aim 1c. Conduct a phase I clinical trial of doxorubicin nanoparticles in patients with lymphoma and evaluate for toxicity the local effects of the injected doxorubicin nanoparticles on the treated node and the development of an anti-lymphoma immune response

Aim 2: Assess the effect of in situ injection of nanoparticles containing both doxorubicin and the TLR9 agonist CpG ODN (CpG dox NPs) on lymphoma cells, the immune microenvironment and the anti-lymphoma immune response

  • Aim 2a. Produce nanoparticles containing doxorubicin and various concentrations of CpG ODN
  • Aim 2b. Assess the toxicity, anti-tumor activity and immune effects of CpG dox NPs in mouse models of lymphoma
  • Aim 2c. Conduct phase I and II clinical trials of CpG dox NPs in patients with lymphoma based on results of studies with the doxorubicin nanoparticles

Aim 3: Assess how agents capable of maintaining the T-cell response impact in situ immunization

  • Aim 3a. Identify and incorporate the most effective agents that maintain T-cell activation, block T-cell checkpoints or block immunosuppressive cells into in situ immunization strategies
  • Aim 3b. Assess whether a systemic or a local blockade of T-cell checkpoints or suppression of T-regulatory cells enhances the efficacy of in situ immunization

Project investigators

Leaders of this Lymphoma SPORE project, all with the University of Iowa, are:

  • George J. Weiner, M.D.
  • Brian K. Link, M.D.
  • Aliasger K. Salem, Ph.D.

The co-investigator is:

  • Alicia Olivier, D.V.M., Ph.D.