The Multitude Of DIPG "Treatment-trials" Choices & The Lack Of Data For All Of Them

Hello, we are just starting and I will be posting all of our findings and thoughts and expand into deep-dive posts for each. But here is the main areas and treatment options/ideas outside of the radiation (standard of care). Some of them are already showing a glimmer of hope and statically outliers/ patients.

Contents:

1. Main Treatment/Clinical-Trials Categories

2. Longer tail of earlier/start-up ideas

3. Add-on treatments (not the first line of defense, but maybe some booster)

My quick summary of the top types of DIPG treatments being tested, trialed or considered as ideas. I will later share my non-profesional understanding of plus and minuses of each. There are close to 100 clinical trials ongoing (maybe the best list of most/all trials) and it is hard to keep track which one are actually recruiting/accepting new patients let alone clearly understanding all the inclusion and exclusion criteria, and how such trials effect your chances of getting into other trials. And there are also many side and add-on treatments and ideas the community is talking about. For new patients I would recommend https://www.mydipgnavigator.org/ for experts guiding you to the best trials, this is mostly for the US, feel free to reach out to us as we are pushing to have a Europe-wide (and hopefully global) equivalent.

1. Main Treatments

• Car-T cells, a type of immunotherapy: multiple locations have trials. Different types of surface proteins being targeted (but only one at a time, so far). Pricy but promising. Main Cons so far is that immune response causes inflammation in the pons and this often sends kids in the ER for a tough recovery. As of 2022 most trials have moved from IV delivery of the Car-T to intercranial (direct delivery to the brain) to minimize the systemic toxicity in other organs.

• "Chemo": various drugs (or combinations) given through an IV, or orally - there are many old and ongoing trials in the range of hundreds (one location that tried to summarize them) we are tracking our own list of drugs and are supporting (clinical and pre-clinical) work to test some of the more promising ones for DIPG in the DIPG/DMG Center Zurich. Some exciting drugs and combinations are being tested after good pre-clinical (in test tubes) trials as well as in-vivo (in mice most often) results.

• There are many subtypes here as various drugs target various things -> your biopsy and DNA/RNA sequencing could provide a lead what could be targeted.

• !!! most drugs are pure repurposing, new drug development (is pricy) for DIPG remains a far hope.

• My personal most promising drugs: ONC201 and/or Paxalisib; Selinexor; Oral AMXT 1501 in Combination With IV DFMO (I have concerns with DFMO passing the BBB, but in mice trials have shown tremendous results (maybe with CED and/or BBB opening combination?)

• Drug repurposing is ongoing, novel targeted drug development remains too expensive.

• OncoVirus - special viruses (ex. DNX-2401 Oncolytic Adenovirus single site Phase 1 trial results) that infect only cancer cells with direct to tumor delivery: no open trials as of today. (2023 might be positive to have at least one trial, but there are challenges). There is a discussion if stem-cells loaded onco-virus (ex. Calidi Biotherapeutics) is better vs. the naked virus DNX-2401. For DIPG we seem to only have naked-virus information, GBM has wider options.

• CED (Convection Enhanced Delivery) - directly infusing (with catheter(s)) some drug/chemo into the tumor. Very similar procedure as the brain tumor biopsy (often done/advisable to be done at the same time). Benefit: bypass the BBB (Blood Brain Barrier) and remove most of the systemic toxicity. Trials with CED delivery have to be done per drug thus the technique, although very promising, remains to be approved for general use. Best leads:

• Mark M. Souweidane, M.D the leader in the space for years with good success and most data.

• neuroinfuse™ drug delivery system great tech allows multiple infusions with up to 4 catheters (better coverage of the tumor), but there has not been a push/support to get a real clinical trials going. 7+ Compassionate Care cases in the UK

• Drugs considered/tested MTX110 (Panobinostat) NCT03566199, NCT04264143

• As of March 2023 NCT05063357 is enrolling patients for CED of the drug 131I-Omburtamab

• Focused Ultrasound FUS (see full blog) - new but promising (various use cases) some clinical trials are ongoing.

• 1. microbubbles to temporarily open a selected section of the BBB and allow drugs to enter the brain as a start or in larger quantities (for the BBB penetrating drugs).

• 2. Sonodynamic therapy: "a tumor-binding-targeting drug (SONALA-001) together with MR-guided focused ultrasound as sonodynamic therapy (SDT)" Promising, a trial in Washington DC is ongoing, promising with the potential of some efficacy without side effects and innervations . Efficacy and long-term effects are still TBD. A competitor not requiring MRI guidance also exists but it is currently not targeting DIPG (we have started some discussions there). Main question for me remains does the 5ALA

• Vaccines: Previous trials have not published or indicated great results (ex. H3.3K27M Peptide Vaccine With Nivolumab). But the hope that some of the new trials will yield something positive remain (ex: rHSC-DIPGVax Plus Checkpoint Blockade)

2. Longer tail of earlier/start-up ideas

The longer tail of new devices and ideas that could be SciFi amazing in start-ups of pre-clinical research.

• Hype fraction Radiation: take smaller doses of radiation: for example 1 week at a time, but repeat it as needed. An ongoing trial(s) exist , but no previous supporting data that it is better than the current standard of care. March 2023 recruiting trial: NCT05077735

• RADIO FREQUENCY ENERGY (ulRFE) SPECTRUM: Nativis Voyager device (maybe this is the old name) tries to "directly influence metabolic pathways" by measuring the specific electromagnetic fingerprints of a molecule and record their molecular “song.” Which then get replayed by a coil worn by the patient. Ref: EMulate Tx . In short, they record the ghost of the drug and then replay this without having to actually take the drug: this has a much wider application than DIPG, and we at Swiss to Cure DIPG have funded some pre-clinical work in UCSF to get an idea on the efficacy in mice bearing DIPG. It should work with any drug that work by non-covelantly binding (just by exchange electro-magnetic signals) with patient cells: this should represent over 50%-66% of all currently used drugs.

• Tumor Treating Fields (TTF): new to the DIPG/DMG there is a new study opening for that with radiation, but placement of electrodes has been a challenge for DIPG since ~2014, when I found the initial company references. Device name is Optune® "uses alternating electrical fields to disrupt tumour cell division, or cause cell death, thereby preventing the tumour from growing or spreading so quickly"

• Quantum Magnetic Resonance Therapy: Cytotron® looks like an MRI, a device from India. Limited references or recent activity. Example 1; Ref 2

• DNA Repair: try to repair or change the DNA of the DIPG cells: more to come later.

• Reduce/eliminate the Radiation Resistance of the DIPG cells: drugs/methods to. A number of clinical and pre-clinical work is ongoing here. A recent publication mentions one responsible gene being discovered, I have overheard for 3 genes being identified (but not yet published)

• “human alpha-lactalbumin made lethal to tumour cells” (HAMLET): Breast-milk molecule by Hamlet Pharma by "a complex from human milk that induces apoptosis in tumor cells but spares healthy cells" The company has been mainly financed by private funds and grants and given some possible ethical concerns has been slow to progress. We are looking if we can jump-start that?

• ...

3. Add-on ideas (nor primary treatment so far)

Add-on ideas that do not have any solid clinical data proving efficacy, dosage and/or safety for DIPG/DMG but are commonly used and discussed But dosage varies widely and efficacy is based in self-reported cases or they have very limited pre-clinical only tests (eg. CBD)

• CBD &/or THC/CBG (see fully blog post here) - pre-clinical trials show CBD killing cancer/DIPG cells (dedicated blog for CBD/THC/CBG linked above). THC remains questionable as the high-effect as well as not clinical proves of efficacy.

• Turmeric and Curcumin as a food supplement, but also as special set of molecules in FDA registered drug(s) currently being trialed for GBM and other head and neck tumors like avetabiomics.com's APG-157 drug (we are starting dome pre-clinical testing and combination testing on DIPG cell-lines )

• Diet: Ketogenic Diet or No animal(Methionine Restrictive Diet) products diet or ... (I am still looking into that, but for kids it could be a stretch and risky based on some papers that I've read and expert opinions). On the other side I've seen long(er)-term servitors beating the odds using it ...

• Keto Diet (really a modified Atkins Diet, as real Keto is not feasible for kids and required at least 1 week in-patient set-up) has been recommended as an add-on to the Onc201+Pax combination.

• No-animal products (Methionine Restrictive Diet) was mentioned as best option for patients Onc201 only. Example (1 min video) results of recently funded research by Dr. Cinthia Hawkins in mice.

• Large list of food supplements ... some might have liver risks or contradictory effects to current treatments as there have not been any pre or clinical official data on pharmacokinetics.

• Oxygenated water - does not seem very useful, but it is not harmful based on those 2 publications

• "Drinking of oxygenated water possibly leads to a time-limited, yet very moderate, systemic generation of radicals. Regular consumption of oxygenated water over a longer period of time seems to attenuate this effect. The mechanisms leading to this effect and adaptation are unknown."

• "Conclusion: Long-term consumption of oxygenated water has no apparent harmful effect on the liver, blood and the immune system. Moreover it leads to a transient moderate increase of oxygen radicals in the blood. An interesting observation is the increase of the Th1/Th2-ratio in the Verum group, whereas in both groups T-cell activation after mitogen stimulation, the soluble IL-2 receptor, the CD4+ and the naive CD4+CD45RA+ cells increased."

• Trial with not publishing results: NCT02688452 you decide what this means :)

• ...

If you have other ideas please do share and I will add more links and details for each (maybe in separate posts)

Other variations when the treatment is administrated

1. Before/after/during radiation

2. Before/after/during biopsy (with or without biopsy)

3. After relapse/recurrence/progression of the tumor: something was done, maybe there was stable period, but the tumor worsens or spreads.

Good source for list of clinical trials:

• Main source: https://clinicaltrials.gov/

• Best effort to track and summarize: https://dipg.org/dipg-treatment/active-clinical-trials/

• DMG-Act for data sharing across global experts: https://dipgcenter.ch/dmg-act/

We as Swiss to Cure DIPG remain confident that some combinations of some of the areas above (or new ones) will bring a light at the end of the tunnel and continue supporting targeted research, trials and connecting promising ideas to DIPG experts.