Workshop on Enhancing Systemic Drug Delivery in Cancer (Abstracts)

SESSION 1: How to Deliver Cancer Therapies- Different Modalities, Different Needs

Enhancing drug delivery in cancer prostate cancer
William Dahut, MD, National Cancer Institute
Drug delivery remains a significant issue in the effective treatment of patients with malignancies. In this presentation Prostate Cancer will be used as a model to show the wide range of issues that interfere with effective systemic delivery. Tumor heterogeneity, changing patterns of tumor cells in response to prior systemic therapy and the difficulties of off target toxicities in men treated with targeted therapies will be discussed. Recent data on the use of PSMA radioligands will be highlighted as means to discuss evolving treatment strategies.

RNA-based therapies toward improving cancer therapy
Anil K. Sood, MD, M. D. Anderson Cancer Center
Since the discovery of RNA interference (RNAi), interest in using this technology for clinical applications continues to grow. Although small molecule inhibitors and monoclonal antibodies have led to successful therapies for cancer, many important cancer therapy targets are difficult to inhibit using these strategies. Use of short interfering RNA (siRNA) as a method of gene silencing has rapidly become a powerful tool in protein function delineation, gene discovery, and drug development. Recent approvals of RNAi drugs by the FDA for human diseases raises hopes that such therapies will have broader applications for many other diseases, including cancer. In vivo delivery of RNAi drugs for cancer applications has proven difficult and many physiological obstacles stand in the way of successful and efficient delivery. To overcome these limitations, we and others have developed biocompatible nanoparticle strategies for effective delivery of siRNA. We have used a novel complex of siRNA with a neutral nanoliposome (1,2-Dioleoyl-sn-Glycero-3-Phosphatidylcholine - DOPC) for in vivo siRNA delivery. This delivery platform has shown substantial efficacy with regard to target modulation and anti-tumor effects in many different tumor models and is currently being tested in a Phase I clinical trial. In other work, we have tested new approaches to stabilize siRNA, and developed approaches for targeted delivery and sustained delivery. To target the tumor microenvironment, we have also developed delivery methods for targeting both tumor cells as well as tumor associated endothelial cells. Collectively, these approaches offer new opportunities for therapeutic gene silencing and hold promise for clinical development.

Targeted radionuclide therapies
Neeta Pandit-Taskar, MD, Memorial Sloan Kettering Cancer Center
Radionuclide therapies have been used in the treatment management of cancers for several decades such as Radioactive iodine therapy for thyroid cancer. FDA approval of agents such as xofigo and lutathera and advances in theranostics has led to preclinical or clinical development of novel radio-targeted ligands, antibodies and antibody fragment for therapy. These agents are approved for treatment of metastatic disease and administered systemically for their ability to deliver radiation to widespread lesions. However, the systemic distribution also leads to several challenges especially pertaining to side effects. While aim is to maximize delivery of radiation to tumor is key, limiting the exposure of normal organs to radiation within defined limits is critical. Personalized dosimetry approaches can help optimize tumor to normal organ doses. Theranostic companion imaging component helps establish tumor targeting and dosimetry estimations, however can be practically challenging depending on the radionuclide used especially alpha emitters. Localized therapies to deliver radiopharmaceutical delivery to an organ or a compartment can enable delivery of larger radiation doses with low systemic toxicities. This technique has been used for treatment of liver metastasis. Localized or compartmental approaches can be a significant advantage in pediatric population. At our institution, we have utilized compartmental delivery of radioimmunotherapy for several tumors such as DSRCT and leptomeningeal disease from NB or medulloblastoma. Intra-tumoral delivery, intraperitoneal or intraventricular delivery allow for focused delivery to disease within a compartment with lower systemic side effects. Other mechanisms of enhancing delivery included combination treatment with radiosensitizers or those that mechanistically enhance physiological process of uptake within tumors. Assessment of presence of appropriate target and target occupancy by thee therapeutic can help optimize delivery of personalized therapy.

SESSION 2: Drug Delivery Technologies

Theranostics in delivering and monitoring cancer therapies
Jordan J. Green, PhD, Johns Hopkins University
There is great interest in the development of improved methods to monitor cancer in patients. From early diagnostic detection to the evaluation of the biodistribution and efficacy of advanced therapeutics, molecular imaging plays a key role. Imaging modalities include magnetic resonance imaging, computed tomography, positron emission tomography, single photon emission computed tomography, optical imaging, and ultrasound, each with their own strengths and limitations. Cancer imaging agents span a range of length scales from chemical small molecules, to biological proteins, to larger engineered nanostructures. Nanostructures are particularly of note as they can be engineered to contain both therapeutic and imaging/diagnostic modalities together, creating theranostic devices. Delivery remains a challenge as physiological barriers, and in some cases intracellular barriers, must be overcome. Through design, engineered nanostructures can cross these delivery barriers and cancer targeting can be increased through tuning of physical properties, incorporation of ligands, and in the case of genetically-encoded agents, transcriptional control of expression. Imaging modalities vary in their sensitivity, spatial resolution, and temporal resolution, and imaging agents and delivery devices must to be designed to be biocompatible and safe, in addition to being effective. Theranostic devices have great clinical potential for both treatment and real-time, non-invasive monitoring of effectiveness. Challenges and opportunities for theranostics and their delivery will be discussed.

Nucleic acid delivery systems for RNA therapy
Daniel G. Anderson, PhD, Massachusetts Institute of Technology
High throughput, combinatorial approaches have revolutionized small molecule drug discovery. Here we describe our work on combinatorial development of RNA delivery systems. Libraries of degradable polymers and lipid-like materials have been synthesized, formulated and screened for their ability to delivery RNA, both in vitro and in vivo. A number of delivery formulations have been developed with in vivo efficacy, and show potential therapeutic application for the treatment for a range of diseases. Here I will describe in particular how advances in the delivery of RNA can be applied for the treatment of cancer.

A new generation of multimodal targeted therapies for cancer
Philip S. Low, PhD, Purdue University
We design, synthesize, test, and translate “smart drugs” that are targeted specifically to cancers and other pathologic tissues. More specifically, to avoid the toxicity that commonly plagues potent drugs that accumulate in healthy cells, we link these potent drugs to homing molecules that carry them selectively to cancer cells. Concentration of the targeted drugs in the cancer cells, together with the limited (if any) retention of the targeted drugs in healthy cells then assures both the maximal potency and safety of the drug. In my talk I will first show how tumor-targeted NIR fluorescent dyes can significantly enhance a surgeon’s ability to find and resect all malignant lesions during cancer surgeries. I will then demonstrate how two different tumor-targeted radiotherapeutic agents can eradicate tumor cells without damaging adjacent healthy cells. I will finally document how targeting of appropriate drugs to specific immune cells and cancer-associated fibroblasts in the tumor microenvironment can dramatically suppress tumor growth in virtually all solid tumors.

Nano-chemotherapeutics in oncology: focus on liposome-based drugs
Alberto A. Gabizon, MD, PhD, Shaare Zedek Medical Center, Hebrew University-School of Medicine, Jerusalem, ISRAEL
Nanoparticles can provide effective control of the release rate and tissue distribution of their drug payload, leading to major pharmacokinetic and pharmacodynamic changes vis-à-vis the free drug. Liposomes are among the most frequently used nanoparticle systems for parenteral delivery of drugs. Pegylated liposomes are of particular interest because of their prolonged circulation time and enhanced accumulation in tumors via the enhanced permeability and retention (EPR) effect. Several liposome formulations of chemotherapeutic drugs have been approved for the treatment of cancer and many others are in clinical testing including: pegylated liposomal doxorubicin (Doxil/Caelyx®, and generic versions) which is the first and most widely used cancer nanomedicine and has demonstrated clinically a favorable safety profile with an impressive reduction in cardiac toxicity and is approved for a broad array of indications; Onivyde®, a partially pegylated liposome formulation of irinotecan approved for treatment of pancreatic cancer; Vyxeos™, a dual drug liposomal formulation with co-encapsulated cytarabine and daunorubicin at an optimized ratio to obtain a synergistic effect, approved for treatment of AML; Promitil®, a pegylated formulation of a lipidic prodrug of mitomycin-c, in early phase clinical studies, with a 3-fold reduction in toxicity as compared to free mitomycin-c and powerful radiosensitizing properties.

Liposome-based nanomedicines offer a unique tool for other manipulations including modulation of the immune system by exploiting the affinity of liposomes for macrophages, grafting of tumor-specific ligands for active targeting to tumor cells and enhanced intracellular drug delivery, and co-encapsulation with radionuclide chelators for real time PET imaging of liposome fate and biodistribution in cancer patients. We have demonstrated that pegylated liposome-entrapped alendronate (PLA), an amino-bisphophonate, can abrogate tumor-promoting effect of macrophages and result in a significant in vivo boost of the antitumor activity of gamma-delta T cells. When doxorubicin and alendronate are co-entrapped in pegylated liposomes, complementary chemotherapeutic and immunotherapeutic anti-cancer effects are elicited resulting in a highly potent formulation. Furthermore, the combination of nano-chemotherapeutics with immune checkpoint inhibitors, particularly when using immunogenic cell death-inducing drugs, has a strong biological and pharmacological rationale and is yet to be explored in the clinic.

The answer to how we enhance systemic drug delivery in cancer treatment lies within the question
Laurent Levy, PhD, Nanobiotix, Paris, France
How we enhance systemic drug delivery in cancer treatment is a large and noble question. Nanobiotix is challenging the premise through the principles of nanophysics. With the goal of improving treatment outcomes in mind, Laurent Levy and his team postulate a shift in approach that would alter the current paradigm of drug delivery.

Nanobiotix is developing a radioenhancer, consisting of modified hafnium oxide nanoparticles, that is delivered intratumorally. The technology—NBTXR3—has achieved proof of concept in a phase III study showing that its novel mechanism of action absorbs an increased amount of energy within tumor cells and delivers an enhanced radiotherapy dose, which induces significant physical destruction of tumor cells without increasing damage to surrounding healthy tissues. The Company is currently evaluating NBTXR3 for patients with head and neck cancer in a phase I dose expansion study, and has a phase III global registration study launch planned for this year. Early clinical evidence from a phase I study evaluating NBTXR3 plus anti-PD-1 as a local and systemic therapy suggests that NBTXR3 can destroy the injected tumor; prime adaptive immune response; improve the efficacy of anti-PD-1; and help overcome resistance to anti-PD-1 as well.

Additionally, Nanobiotix is seeking to change the paradigm of systemic drug delivery through wholly-owned subsidiary, Curadigm. Curadigm’s novel “nanoprimer” technology aims to overcome the challenges that intravenously-administered therapeutics face by directly targeting the liver. The nanoprimer is delivered via IV, prior to the therapeutic, temporarily occupying clearance pathways in the liver so that a higher percentage of the effective dose can reach the target without adding hepatic toxicity. Nanobiotix sees far-reaching implications for this technology in oncology and in any disease where IV therapeutics have an opportunity to help patients.

The Company has also invented a third nanotechnology platform that is being applied to CNS disorder.

Antibody-Drug Conjugates: current status and future directions
John M. Lambert, PhD, consultant, former CSO of ImmunoGen, Inc. (2008-2015)
Antibody-drug conjugates (ADCs) are an emerging class of cancer therapeutics constructed from monoclonal antibodies that have selective binding to targets on the surface of cancer cells conjugated with small molecule cytotoxic agents. Successful application of this concept should yield ADCs that have a wider therapeutic index than that afforded by small molecule cytotoxic compounds (“classical” chemotherapy). Since the initial approvals of brentuximab vedotin (Adcetris®) in 2011 and ado-trastuzumab emtansine (Kadcyla®) in 2013, there has been an explosion of research in the field, with more than 100 ADC compounds in clinical evaluation at the end of 2020. To date, nine ADCs have been approved by FDA for both hematologic malignancies and for solid tumor indications.

All three components of an ADC, the antibody, the cytotoxic agent, and the linker that joins them, are critical elements in its design. Besides an antibody moiety specific for a target expressed on cancer cells, the cytotoxic payload must be sufficiently potent to be able to kill cells at doses that can be delivered by antibody-mediated targeting. The linker component of an ADC should be sufficiently stable in circulation, yet should allow efficient release of a cytotoxic metabolite once the ADC reaches the cancer tissue and is taken up into cancer cells. Furthermore, while all the approved ADCs employed stochastic conjugation chemistry to join linker-payload to an amino acid side chain of the antibody, several site-specific conjugation chemistries are now often used in ADCs, with several now in clinical evaluation. Building on the advances in medicinal chemistry to build a large “chemical toolbox” for ADCs, innovation in the field is turning towards the target/antibody biology. The seminar will highlight the complexity of ADCs and the interplay between payload class, linker chemistry, target antigen, and other variables that determines efficacy in a given setting.

Innovation in nano-delivery constructs
Samir Mitragotri, PhD, Harvard University
Nanoparticle-based drug delivery systems are widely explored to improve the biological outcome of chemo and immunotherapy. However, poor vascular circulation, limited targeting and the inability to negotiate many biological barriers are key hurdles in their clinical translation. Biology has provided many examples of successful “carriers” in the form of circulatory cells, which routinely overcome the hurdles faced by synthetic nanoparticle systems. Our laboratory has explored blood-cell inspired nanoparticle delivery systems that take advantage of the abilities of red blood cells and macrophages. We have explored cellular hitchhiking which involves combining synthetic particles with circulatory cells to drastically alter the in vivo fate of the synthetic particles. I will provide an overview of the principles and two examples of hitchhiking-based nanoparticle delivery.

SESSION 3: Cancer immunotherapy – delivery and treatment outcomes

Improving the efficacy of immune checkpoint inhibitors through combinations with radiotherapy
Zachary Morris, MD, PhD, University of Wisconsin
Pre-clinical and clinical evidence provides rationale for combination of radiation therapy with immune checkpoint blockade. Radiation can simultaneously promote adaptive immune recognition of tumor cells and tumor evasion of immune rejection via upregulation of PD-L1 on tumor cells. The addition of checkpoint blockade can overcome this resistance mechanism and enable the generation of a systemic anti-tumor immune response. Combination of immune checkpoint inhibitors with radiation may be particularly valuable in the treatment of immunologically “cold” tumors, which are characterized by low levels of T cell infiltrate and low mutation burden resulting in few mutation-created neo-antigens. Such “cold” tumors do not typically respond to immune checkpoint inhibitors alone. Even in tumors that are responsive to immune checkpoint blockade, radiation may allow for increased depth and duration of response by priming a more diversified adaptive anti-tumor immune response. These observations have stimulated multiple clinical studies testing combinations of radiation and immune checkpoint inhibitors. Next-generation approaches using alternative approaches to radiation therapy or combining additional classes of immunotherapies with radiation are being developed now in preclinical studies to improve upon and further leverage the in situ vaccine effect of radiation to enhance development of anti-tumor immunity in combination with immune checkpoint blockade.

Use of the silicasome platform for pancreatic cancer chemo-chemoimmunotherapy through the delivery of irinotecan and DACH-platinum
André Nel, MD, PhD, California NanoSystems Institute, University of California, Los Angeles, California
Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease treated by two major drug regimens, gemcitabine and the 4-drug combination known as FOLFIRINOX (oxaliplatin, 5-fluorouracil, irinotecan, and leucovorin). In addition to the contributions of late diagnosis and early metastatic spread to the mortality, a major treatment obstacle is the abundant dysplastic stroma, interfering in drug access as well as in antitumor immune responses. While FOLFIRINOX leads to better survival outcome, the high toxicity of irinotecan and oxaliplatin frequently precludes use FOLFIRINOX as a first-line treatment option. For this reason, we have developed a lipid bilayer coated mesoporous silica nanoparticle (MSNP) carrier, a.k.a. a silicasome, to improve the delivery and safety of irinotecan in orthotopic PDAC tumors, demonstrating that it can significantly outperform the liposome, Onivyde. Not only are the silicasomes more stable than the liposome, but allows transcytosis access to the PDAC site. We now demonstrate that in addition to its topoisomerase I inhibitory activity, encapsulated irinotecan exerts a major additional effect on lysosomes, where early alkalization interferes in lysosome fusion with the autophagosome. The accompanying accumulation of damaged organelles and unfolded proteins by autophagy flux interference, triggers endoplasmic reticulum stress, culminating in the generation of a novel form of immunogenic cell death (ICD). The ICD response is accompanied by increased PD-L1 expression, prompting us to investigate whether the irinotecan can also be used to impart immunogenic stimuli to the treatment with the silicasome in orthotopic KPC tumors, using a syngeneic animal model. Not only did we observe irinotecan-induced enhancement of cell stress and cytotoxic T-cell responses at the PDAC site, but the ICD effect could be augmented by co-delivery of anti-PD1 mAb. This resulted in significant improvement in survival outcome, including comparison making to Onyvide. In another set of experiments, we also investigated the known ICD-inducing effects of oxaliplatin, which was hindered initially due to inefficient drug loading into the silicasome. This inspired the synthesis of an activated form of oxaliplatin (DACHPt), which allowed us to use coordination chemistry for drug attachment to MSNPs silanol groups under alkaline conditions. Subsequent coating with a lipid bilayer allowed effective generation of ICD responses by the DACHPt-silicasome in orthotopic PDAC tumors. As for irinotecan, the response could be enhanced by co-treatment with anti-PD1. In summary, we demonstrate effective strategies for using ICD-inducing chemotherapy in the silicasome platform, allowing us to significantly augment the chemotherapy response to two FOLFIRINOX drugs by additional immunotherapy.

Enhancing CAR T cell delivery and cells as enhanced drug delivery vehicles
Marcela Maus, MD, PhD, Massachusetts General Hospital Cancer Center and Harvard Medical School
T cell therapy has emerged as transformative therapy for blood cancers. Autologous and allogeneic T cells that have been genetically modified to express a chimeric antigen receptor, or CAR, have been shown to induce long-term remissions in patients with B-cell lymphoma, B-cell leukemia, and Multiple Myeloma. The delivery of cell-based therapies, whether autologous or allogeneic, is complex and requires collection, processing, and tracking systems that result in significant challenges to patients, their doctors, and the healthcare system. On a systems note, we will discuss the current clinical status of CAR T cell therapies and prospective delivery technologies that could enhance scalable and effective clinical care. On a scientific note, we will discuss how cell-based therapies can be engineered and used as a platform to deliver multiple therapeutics at once, and achieve local infiltration and concentration in specific compartments or wider systemic distribution.

Enhancing cancer immunotherapy using nanomedicine approaches
Darrell J. Irvine, Koch Institute, MIT; Scripps CHAVI-ID, Biological Eng. and Materials Science & Eng., MIT; Ragon Institute of MGH, MIT, and Harvard; HHMI
The use of formulation design and materials chemistry to control the timing, dose, and location of delivery of immunostimulatory cues is a powerful strategy to enhance immunity induced by vaccines and cancer immunotherapies. Two examples of our recent work utilizing such approaches will be highlighted: First, we recently developed a strategy to enhance chimeric antigen receptor (CAR) T cell therapy for cancer, via targeted delivery of ligands for the CAR T cell to lymph nodes to “vaccine boost” CAR T cells: By attaching a small molecule, peptide, or protein ligand for a chimeric antigen receptor (CAR) to amphiphilic albumin-binding PEG-lipids (forming an “amph-vax” molecule), CAR ligands could be delivered efficiently to lymph nodes by albumin and subsequently partition into membranes of resident antigen presenting cells, thereby co-displaying a CAR T cell ligand from the cell surface together with native cytokine/receptor costimulation. We show that this approach effectively concentrates CAR T ligands on the surfaces of dendritic cells in lymph nodes, leading to profound expansion of amph-vax-boosted CAR T cells in vivo. In a second example, we have studied self-assembled PEGylated lipid nanodiscs (LND) as carriers to systemically deliver STING agonists (cyclic dinucleotides, CDNs) into tumors. Compared to state-of-the-art liposomes, i.v.-administered LNDs carrying CDN-PEG-lipid (LND-CDNs) exhibited more efficient penetration of tumors, exposing the majority of tumor cells to STING agonist. A single dose of LND-CDNs induced rejection of large established tumors, coincident with immune memory against tumor rechallenge. Although CDNs were not directly tumoricidal, LND-CDN uptake by cancer cells was essential for robust T cell activation by promoting CDN and tumor antigen co-uptake by dendritic cells. LNDs thus appear promising as a vehicle for robust delivery of compounds throughout solid tumors, which can be exploited for enhanced immunotherapy.