We pioneered the first linac based intensity modulated total marrow irradiation (IMTMI) and demonstrated outcome benefits through clinical trials.

The utilization of radiation as a part of conditioning regimens prior to bone marrow transplant in hematological malignancies has been steadily decreasing over the years due to its toxicity. Nevertheless, relapse and poor response to chemotherapy are still very despite the advances. Furthermore, prognosis get worse with each successive transplant. For instance, our institutional historical 2-year overall and progression free survival for AML receiving second transplant are currently 23% and 18%, respectively. We pioneered the first linac based intensity modulated total marrow irradiation (IMTMI).  Our work focuses on 1) technically to improve it from being a challenging treatment to a clinically feasible technique that can be used routinely in busy clinics to enable clinical trials and 2) clinically to foster collaborations to elicit clinical trials and to recruit more patients. These efforts resulted in 1) the completion of our first two clinical trials in AML and MM, for which, and publish promising results in 2015 and 2018, respectively. These studies provided the clinical evidence base for the feasibility and tolerability of adding IMTMI to the standard of care transplant regimens in advanced diseases. Based on these encouraging results we have opened two follow up Phase II studies, one for AML and one for MM which are currently accruing patients. In addition, we have recently published results of our last Phase I study which sought to prospectively determine the role of TMI in advanced AML patients who are receiving second or higher transplant. This study demonstrated that adding TMI to standard of care has the ability to substantially improve both 2 years OS (50%) and PSF (48%) compared to our historical outcome data of 23% and 18%, respectively. To date, we have treated over 150 patients, which is the largest patient cohort treated with this technique.

Metastases remain the leading cause of cancer-related mortality. However, recent studies have reported promising outcomes in clinical trials using multi-site ablative therapies, especially when all sites of disease were treated. Furthermore, the oligometastases hypothesis postulates that a spectrum of metastatic spread exists and that some patients with a limited burden of metastases can be cured with ablative therapy. A good portion of metastatic cancer patients are inflicted with aggressive disease and either travel long distances or are not healthy enough to commit to multiple days of treatment. Even one day can make a substantial difference in treatment outcomes in this overly aggressive disease setting. Nevertheless, as the planning complexity increases, such as in SBRT of multiple metastases, the lead time for RT may also increase up to 10 business days. An efficient workflow/RT technique to deliver the first treatment fraction within a few hours may not only improve outcome but also facilitates its widespread implementation as an effective treatment strategy for treating both palliative and curative diseases.

Our lab is working on with advanced adapative treatment planning strategies to streamline the planning process and provide an on-table (online) workflow for these time critical cases.  This includes automated contouring, highly optimized templates for rapid and robust plan generation and efficient optimization and review.

Top row standard plan.  Bottom row adaptive plan.

Clinical RT has developed rapidly over the past decades. Treatment planning was initially 2D, based on radiographs or external features. Technological advances including MRI and CT imaging, inverse planning, and IMRT first realized with patient-specific compensators, which varied the intensity within beam apertures, and later multi-leaf collimators (MLCs) that arbitrarily shape/modulate fields, radically improved the conformality of dose to diseased tissues and reduced complications. The precision provided by IMRT has enabled more effective treatment methods such as simultaneous integrated boosts (SIB) to radioresistant regions within a given tumor. Modern developments in functional imaging techniques, including PET, SPECT, and MRI offer potential to identify radioresistant tissue regions by probing pathophysiological features of tumor tissues such as metabolism, tumor cell proliferation, hypoxia, and perfusion. Molecular imaging methods are being applied to study tumor biology at the genotype and phenotype level to further unravel tumor heterogeneity. This wealth of new information presents a tremendous opportunity to identify regions within a tumor volume with differing sensitivity to radiation dose. The dose-painting hypothesis suggests local control could be improved by treating biologically defined target volumes with a nonuniform dose by sub-volume boosting or dose-painting-by numbers as opposed to the current paradigm of uniform treatments to anatomically defined targets. Preclinical studies are warranted to test this hypothesis. Unfortunately, preclinical irradiators are currently limited to open field treatments making them unsuitable for dose-painting precise tumor sub-regions due to poor dose conformality.

Our work has developed techniques for developing IMRT treatment plans for small animals, developing models of compensators to achieve the necessary fluence modulation suitable for rapid fabrication with 3D printing using metal loaded plastics.  This cutting edge approach enables a range of preclinical studies, of which our group has a specific interest in personalized radiation therapy plans developed using functional imaging to address local variations in tumor physiology and microenvironment, see our other work on oxygen guided radiation therapy.

Planning study results showing the conformity index is shown for IMRT and conformal techniques. Dose conformity about the hypoxic volume to be boosted was highly significantly improved with use of IMRT versus CRT.

Clinical radiation therapy is a noninvasive means to mitigate cancer progression, which is prescribed for more than 50% of prostate cancer patients. Development of radiation technology, such as utilizing intensitymodulated radiotherapy (IMRT) to deliver highly conformal radiation dose distributions and image-guided radiotherapy (IGRT) to account for daily changes in target anatomy and positioning, allows unprecedented levels of accuracy and therapy outcome. The prostate is surrounded by many nerves and muscle fibers controlling different excretory and erectile functions that are difficult but necessary to avoid, it still remains a challenge to precisely deliver radiation doses to prostate cancer without damaging the normal surrounding tissues even with image guidance. To avoid excessive irradiation doses, radiosensitizers have been developed to amplify the effects of radiation within tumor cells. Prostate cancer targeted radiosensitizers may offer a means for further relative biological dose escalation with sparing of normal tissue. However, there has been limited preclinical and clinical investigation of targeted radiosensitizers for prostate cancer. To address the challenge, we aim to develop a nanoparticle technology that will improve prostate cancer tissue visualization and discrimination by MRI, allowing greater accuracy in MRI-guided radiation therapy, and provide radiosensitization within the cancer cells.

Prostate specific membrane antigen (PSMA) is an ideal target to detect prostate cancer due to its abundant expression in most prostate cancers. We have synthesized a novel high-affinity ligand for PSMA targeting, and conjugated both targeting ligand and Gd(III) complex to gold nanoparticles and nanoclusters (AuNP/NCs). We have demonstrated that these PSMA-targeted AuNP/NC-Gd(III) have a much higher relaxivity than free Gd(III) agents and the NP/NCs can be selectively delivered to PSMA-expressing prostate tumor cells, providing MR image-guided radiation therapy. By delivering Gd(III) conjugated AuNP/NCs directly to prostate cancer cells we will 1) concentrate the Gd(III) agent to the nanoparticle surface while simultaneously calibrating the delivery of more Gd(III) agent to target tissues and less of the agent to non-specific or off-target sites; 2) improve r1 relaxivity and MR sensitivity, which potentially can reduce the given doses to patients and potentially toxicity of Gd(III) agents; 3) discriminate among cancerous, normal, neural, and muscle cells and tissues with MRI, enabling precise diagnosis of prostate cancer and precision radiation therapy; 4) combine gold and gadolinium together to enhance the radiosensitizing effect for potential ablation of prostate cancer using a lower radiation dose; and 5) enable MRI-guided radiotherapy using MRI LINAC device to enhance radiation accuracy and avoid collateral damage to normal tissues. We believe that this approach will impact the quality and success of radiotherapy. Further, PSMA is also expressed on the neovasculature of a number of different solid tumors, so this approach is proof-of-principal for radiation therapy and ablation for other cancers as well.

Guiding radiation therapy based on local tissue oxygen measurements is critically important as hypoxia (low oxygen) in the tumor microenvironment has been shown to be a strong indicator of increased cancer progression and tumor radiation resistance, so the ability to guide radiation therapy based on local tissue oxygen measurements would potentially improve radiation therapy efficacy. The primary mechanism of radiation is the creation of free radicals that damage the tumor cell DNA. These radicals are neutralized by sulfhydryl containing compounds present in hypoxic cells allowing repair of DNA and leading to treatment failure. Hypoxia radiation resistance is prevalent in most solid tumors, particularly in head and neck, prostate, and cervix. For instance, 48% of all cervical cancers are characterized as hypoxic and those have a reduced 6-year overall survival of 29% compared to 87% for non-hypoxic cases. Overcoming therapy resistance in these cases requires personalized treatment strategies to deliver higher radiation doses to regions with low oxygen levels, increase tumor oxygen levels and optimal time of radiation to enhance effectiveness of radiation therapy. Although the benefits of hypoxia-based treatment prescriptions have been demonstrated in preclinical models, translating these findings into humans has been challenged by the lack of a method to reliably and repeatedly measure oxygen levels within these tumors. Existing oxygen measurement techniques are inadequate for personalizing treatment because they either involve impractical invasiveness or workflow changes, cannot be repeated in a clinically meaningful timeframe, require expensive imaging equipment and trained personnel or provide only indirect and qualitative information.

Our objective is to develop first clinically viable technology for Oxygen-Guided Radiation Therapy (OGRT) to personalize radiation treatment. To achieve this, we will exploit the unique capabilities of electron paramagnetic resonance (EPR) to provide fast, direct, and repeated tissue oxygen measurements to inform clinical decision-making. Electron paramagnetic resonance (EPR) oximetry is an ideal method for measuring hypoxia with its unique capability of rapidly providing precise and absolute tissue oxygenation values without radioactive agents or costly medical imaging systems. EPR uses an oxygen sensing material and an EPR radiofrequency (RF) microcoil to measure local partial pressure of oxygen. EPR can be acquired at a rapid rate, enabling repeated measurements to provide oximetry measurements immediately before and during interventions. The need for invasive implantation has limited its use to relatively superficial tumors (<1cm). We have recently made advances in EPR microcoil technology (patent pending) capable of measuring the local oxygenation levels in deep tumors (~30 cm). This technology will enable personalization of radiation treatments by intensifying treatment in hypoxic regions, thereby enhancing treatment outcomes with reduced toxicity, interventions to enhance tumor oxygen and delivery of radiation at the time of peak tumor oxygen which requires fast and repeated oxygen measurements; that is one of the key strengths of our technology.