During the AACR 2021 session Advances in Drug Delivery and companion panel discussion, speakers discussed new and emerging approaches for the delivery of conventional and experimental drugs, including macromolecule-based immunotherapies, as well as approaches to improve small-molecule drug therapeutic index via targeting strategies.

A recording of the session and the panel discussion will be available to registered attendees through June 21.

Nanomedicines to improve the therapeutic index of targeted medicines

Daniel A. Heller, PhD, Memorial Sloan Kettering Cancer Center, described work involving the transmembrane protein P-selectin as a potential target to enable brain blood barrier crossing for nanotherapeutic delivery to intracranial tumors.

“We know that there is quite a bit of involvement of P-selectin in metastasis,” Heller said. “In human tumors, we’ve stained tissue microarrays and found that, in many human tumors, there is P-selectin expressed in the stroma and endothelial cells and some is even expressed on tumor cells.”

In studying the mechanisms enabling the translocation of nanoparticles across the blood-brain barrier, Heller said they found an important clue in the expression of the protein caveolin-1 (Cav1), a structural protein involved in caveolae that are known to undergo a transcytosis mechanism across endothelia.

“When we give particles and radiation, we see quite a bit of Cav1 expression in the tumor, less in the normal brain,” he said. “If we give the particles only, we still see Cav1 expression, but if we only give radiation, we don’t see that expression of Cav1. This suggests that the particles themselves are causing that Cav1 to light up, further suggesting to us that Cav1 is upregulated upon nanoparticle binding at the tumor endothelium.”

Subsequent findings, he said, suggest that Cav1 is necessary for the P-selectin-targeted particles to translocate across the blood brain barrier.

“P-selectin is needed for particles to bind to the endothelial cell, and Cav1 is needed for the transcytosis mechanism to occur,” Heller said. “This is potentially exciting for a therapeutic mechanism for getting drugs across the blood brain barrier, specifically in the sites of these tumors.”

Ligand-targeted therapies for cancer, autoimmune, and infectious diseases

Philip S. Low, PhD, Purdue University, discussed ongoing work in his lab focusing on the development of targeting ligands that have high affinity and high specificity for receptors that are uniquely or primarily expressed on different disease cell types, including cancer cells.

“Once we have a homing molecule that carries an attached cargo to the disease cell, and we often use therapeutic drugs or imaging modalities that have been developed by others, we try to make good drugs better,” Low said. “With this targeting ligand, we can increase the concentration in the diseased cancer cell while reducing significantly the uptake by healthy cells, thereby improving both the potency and the safety of the drug.”

He noted that they utilize extremely small ligands, which greatly enhances their ability to penetrate solid tumors .

“We have developed targeting ligands for all of the major immune cell types, and this allows us to deliver drugs into these immune cells that can turn on the immune system, turn off the immune system, proliferate these cells, suppress them, and differentiate them,” Low said. “It gives us the freedom to reprogram the immune system in any way we want.”

Antibody drug conjugates: Advances, challenges, and future

Puja Sapra, PhD, AstraZeneca, talked about recent and emerging advances in the use of antibody drug conjugates (ADCs) and their potential for improving efficacy and decreasing the toxicity of conventional chemotherapy.

“With nine approved ADCs in hematological and solid tumor malignancies, antibody drug conjugates are emerging as an important therapeutic modality for cancer care,” Sapra said. “It’s an active field, with more than 90 ADCs currently in clinical trials.”

In order to develop successful therapeutics, multiple components of the ADC molecule have to align, Sapra said, noting that a number of recent ADCs have delivered durable and deep responses.

“These kinds of responses give the field the hope of enriching the future, where ADCs could replace standard of care,” Sapra said. “Beyond cytotoxics, antibody-mediated delivery will be employed in the future to deliver agents, including immunomodulators, radionuclides, oligonucleotides, and targeted therapies.”

Vaccine-boosting CAR T cells through the chimeric antigen receptor

Darrell J. Irvine, PhD, Koch Institute for Integrative Cancer Research at MIT, discussed ongoing work in which he and his colleagues are looking to develop a vaccine-boosting strategy for CAR T cells and studying the impact on antitumor immunity from this treatment approach.

“CAR T cells, when expanded to large numbers, ex vivo and infused into the patient, have been shown to elicit dramatic responses in leukemias and lymphomas,” Irvine said. “But the application of CAR-T cell therapy to more prevalent solid tumors has been met with much more challenging outcomes. So, there is great interest in devising ways to enhance CAR T-cell therapy in the solid tumor setting.”

The investigators sought to determine if CAR T-cell treatment in the solid tumor setting could be enhanced by vaccine-boosting CAR T cells directly through their chimeric antigen receptor in the native lymphoid tissue environment in vivo.

“These vaccine-boosting CAR T-cells then traffic to the tumor site, where they induce robust antigen spreading as well as the release of new tumor antigens that are presented by dendritic cells in the tumor-draining lymph node to new T-cell cohorts that are targeting additional epitopes through natural antigen presentation,” Irvine said. “It’s this combination of synthetic and natural antigen presentation that is leading to the impressive tumor rejection we see for the vaccine-boosted treatment. We’re quite excited about the prospects of this simple vaccine boosting strategy to significantly enhance the activity of CAR T-cell therapy against solid tumors.”