Our approach combining
LTSL-Dox + LITT
Helpful Context: some definitions
Normal Body Temperature: 37°C/98.6°F
LTSL- Dox: Low Temperature Sensitive Liposome Doxorubicin (also called LTLD, and commercially branded as Thermodox) is a special kind of liposome, that encapsulates the anti-cancer drug, doxorubicin, and releases the drug when warmed to just 41°-42°C.
Liposome: Is a tiny ~100nm in diameter lipid membrane bound capsule that can be made to contain a drug, like doxorubicin. Its 100nm diameter is 1,000 times smaller than the diameter of a human hair.
LITT: Laser Interstitial Thermal Therapy is a minimally invasive surgical technique that uses a small laser (central ablation 50°C-80°C, to peripheral hyperthermia 43°C - 45°C) to heat and destroy tumors and unhealthy tissue guided by MRI with near realtime heat thermometry. There are two main commercial systems: Neuroblate at Monteris and Visualase at Medtronic.
HT: Hyperthermia is warming any tissue, especially cancers, to temperatures above body temperature i.e., from about 100°F/40°C to about 113 °F/45°C.
NOTE: LITT is primarily a central-tumor ablative-technology but can also warm peripheral regions of the tumor to these lower hyperthermic temperatures that could release Doxorubicin from intravenously administered LTSL-Dox.
Our Clinical Rationale and Underlying Science
Our Clinical Rationale
We are currently focusing on LTSL-Dox, (current commercial name Thermodox) plus LITT.
What we have already seen in preclinical animal studies is that, when infused intravenously, LTSL-Dox releases its drug in 2 seconds in a tumor vasculature that is warmed to 41-42°C, i.e., LTSL-Dox will treat any tumor that can be heated by any hyperthermic device that can achieve such mild hyperthermic temperatures in a tumor. A paper we wrote in 2001 (1) "The development and testing of a new temperature-sensitive drug delivery system for the treatment of solid tumors" provides a good overview.
Our clinical rationale is:
"if the tumor can be heated, the tumor can be treated"
Confocal fluorescent video microscope video of LTSL-Dox injected via the rat tail vein by Manzoor et al (3), and viewed in the micrcoscope skin flap window chamber, showing 20 minutes of observation in 20 seconds of video time.
Microscopic images of the tumor vasculature in a window chamber by Chen et al, (4) showing the tumor blood vessels before a 1hr treatment with LTSL-Dox + heat, and 24hrs after the treatment. The dramatic result is that all the blood vessels had been shut down and all that was left was a small thrombosis.
Summary of Preclinical Underlying Science
LTSL-Dox cures 11/11 mice
As described in more detail in the later page on "Introducing LTSL-Dox", the first time we tried it in a mouse study, LTSL-Dox cured 11/11 tumors out to 60 days (1), with just a single dose and warming the tumors for just 1 hr.
LTSL-Dox + HT: Dox is delivered throughout whole tumor in 20 mins
To the left is a video of a tumor implanted in a microscopic rat skin flap window chamber warmed to 42°C. It shows how the LTSL-Dox liposomes (green) release their doxorubicin (red) throughout the whole tumor in only 20 minutes of warming (2). Every cell is not only loaded with doxorubicin, but is also in the nucleus of every cell where it kills the cancer.
Thus, our underlying scientific rationale is that,
“the only way to get a drug throughout a whole tumor is to release the drug in the blood vessels of the tumor”.
LTSL-Dox + HT: shuts down tumor blood vessels in 24 hrs
And the black and white images from Chen et al (3), show that, because dox is also delivered into the blood vessel wall cells (endothelial and pericytes), the blood vessels are shut down within 24 hrs after the 1 hr treatment.
LTSL-Dox + LITT and What We Envision
Having shown in the preclinical studies that LTSL-Dox releases its drug at 41-42°C and these temperatures appear to be achievable at the edges of a certain-sized (up to 3cm) LITT-heated tumor, here, we present what we envision where LTSL-Dox + LITT might just make a difference. We then present some information on Brain Cancer and LITT, its successes and, importantly, its limitations that motivate the LITT + LTSL-Dox combination .
Laser Interstitial Thermal Therapy could be combined with an intravenous infusion of LTSL-Dox at an already established dose of 50mg/m^2. Since the in tact LTSL-Dox liposome only has a relatively short half-life of ~1.5 hrs, it is essential for the tumor to be concurrently warmed to target temperature of 41-42°C or the infusion started within a few minutes of starting LITT in the MRI suite.
The goal is to capture the most "Area Under the Curve" for the plasma LTSL-Dox. Shown below is the Mean Plasma Concentration of total doxorubicin vs time in subjects (with liver malignancies undergoing RFA (n = 6) (Wood et al. 2012) (1).
"Could LITT + LTSL-Dox work?"
As we were discussing the LTSL-Dox technology and what we had done over the years, Kate asked the question, "Could LTSL-Dox work with LITT?" i.e., could LTSL-Dox plus LITT provide additional advantages beyond LITT alone? That is, could intravenous LTSL-Dox release its drug triggered by LITT-warming in the impossible-to-remove peripheral regions, that are known to be highly invasive and where recurrence almost inevitably occurs.
As we show in the MRI-brain image below, in the core of the irradiated area, there is virtually instantaneous irreversible cell destruction at temperatures > 60 °C, Then, there is a dynamic thermal reaction (48–60 °C) that can still kill cancer cells. But it is the tissue margins that may suffer none or only reversible cell damage and it is this periphery that becomes a region with a high rate of relapses.
With LTSL-Dox + LITT, while central and medium zones can still have their therapeutic effects, the goals of the new procedure shift to optimal warming of the tumor to 42°C, especially at the periphery. For the right sized tumor (up to 3 cm), LTSL-Dox could, in principle, 'clean up' the remaining tumor cells when the margins are warmed by LITT. We think that this where LTSL-Dox could help eradicate this all-important peripheral cell zone.
Minimally invasive to patient, maximally invasive to tumor
Possible tumor warming scenario for LTSL-Dox + LITT
Our proposal combines a minimally invasive surgical technique with a tested thermally sensitive liposome.
The rings on the image represent the hypothesized treatment layers that would result from this combined approach.
While we intend to go forward using conventional LITT as the first brain tumor-heating modality, we are also considering a reduced ablative approach, i.e., could LITT be used to heat more of the tumor to lower, but still warm enough, temperatures (42°C) to release the doxorubicin throughout the tumor (as in the video above). A less-ablative heating protocol has been suggested by Regenold et al in Christine Allen's group at the University of Toronto (1) where they continue to make a case for LTSL-Dox by using the right heating modality.
Brain Cancer and LITT
While surgical resection does provide some enhancement of Overall Survival (OS), not all tumors are amenable to conventional surgical resection. Even with resection, recurrence is the norm. Data above shows, GBM median survival times as a function of age (3).
The Brain Cancer Problem
According to the Central Brain Tumor Registry of the United States (CBTRUS) (1), the most commonly occurring malignant brain and other CNS histopathology was glioblastoma (14.2% of all tumors and 50.1% of all malignant tumors). Unfortunately, even with the best available treatments, patients inevitably progress and die from the disease. As reported by Mohamed et al, (2) and references therein, "Despite the initiation of aggressive treatment along with extensive surgery, concurrent radiation and adjuvant temozolomide, the median survival time of adult patients remains around 10 months and up to 14 months in patients receiving combined treatment with radiotherapy" And... "Only 3% to 5% of patients survive more than three years, and reports of survival exceeding five years are sporadic".
See also the edited 21-chapter book by Steven De Vleeschouwer, entitled "Glioblastoma" (4).
(4) De Vleeschouwer, S., ed. Glioblastoma [Internet]. 2017, Codon Publications: Brisbane (AU).
In the procedure, (as described at MD Anderson) the catheter is implanted using advanced computer imaging techniques. The laser is guided through the catheter with real-time MRI, allowing neurosurgeons to limit thermal energy delivery only to the tumor. Most patients can go home the day after treatment and can quickly return to normal activities.
An Improved Solution: Laser Interstitial Thermal Therapy (LITT)
As discussed by de Groot et al, (1)"LITT offers a therapeutic alternative for patients with newly diagnosed and recurrent glioblastoma for whom conventional, open surgical approaches are not deemed optimal, whether due to surgical risk or patient preference". And, as pioneered by Sloan et al (2), the NeuroBlate system, with its gas-cooled, end fire or side-firing laser probe, represents new technology for delivering laser interstitial thermal therapy, allowing controlled thermal ablation of deep hemispheric rGBM. It provides patients with a minimally invasive surgical option for recurrent brain tumors, (as well as radiation necrosis and certain types of epilepsy). Several technological enhancements such as MRI thermometry and improved laser probe design have enabled feasibility and improved the safety of LITT procedures (3).
As shown above (Possible tumor warming scenario for LTSL-Dox + LITT), ablation temperatures right next to the probe (central zone where early liquefactive necrosis occurs) ranges between 50 °C and 80 °C. And then the temperature drops off, as the inverse square law, (so 1/radius^2) down to body temperature (4) . In this peripheral region, where temperatures can be between 43 °C and 45 °C for more than 10 min, the cancer cells are sensitized to chemotherapy and radiation therapy, but not necessarily killed.
(3) Patel, B. and A.H. Kim, Laser Interstitial Thermal Therapy. Mo Med, 2020. 117(1): p. 50-55.
Thermal Damage Threshold (TDT) lines. Image from Kamath et al 2019, (7) , during laser ablation, demonstrating tumor volume (constructed manually on Monteris® [Plymouth, Minnesota] proprietary software at the time of surgery) and yellow and blue thermal damage threshold (TDT) lines (derived from real-time MR thermometry).
LITT Nevertheless has Limitations...
As also reported in the paper by de Groot et al (1), while studies have demonstrated strong safety data for LITT there is variable efficacy in subgroups of patients. "In 29 new and 60 recurrent grade 4 glioblastoma patients the median overall survival (OS) was 9.73 months for newly diagnosed patients and median post-procedure survival was 8.97 months for recurrent patients".
Despite median physician-estimated extent of ablation of 91%-99%, tumors still progressed. The infiltrated cancer cells for GBM tumors make it difficult for surgeons to surgically and completely resect the whole tumor or to fully ablate with LITT. In the picture shown to the left from Kamath et al, (2) in their phase 1 trial testing times and temperatures, there are areas outside of the yellow Thermal Damage Threshold (TDT) line that miss the pink border outlining the tumor. It’s these external margins that cause the GBM tumors to grow back so consistently in patients.