It's been known for a number of years that certain oncolytic viruses can target both bulk cancer cells as well as CSCs. Engineering in interleukin 12 in one of them produced a significant but modest improvement in survival http://www.pnas.org/content/110/29/12006.long Immune checkpoint inhibitor antibodies alone (either anti-PD-1 or anti-CTLA-4) produced only modest improvement in survival, similar to the virus, while the combination of virus with either antibody further extended survival. However, the triple combination cured ~90% of mice and protected them from re-challenge http://www.cell.com/cancer-cell/fulltext/S1535-6108(17)30298-2
Now a Phase I trial using the virus alone is ongoing https://clinicaltrials.gov/ct2/show/NCT02062827
critic, what I have been wondering about lately is what would happen if an oncolytic virus were packaged in chitosan? If there were a way to make the virus invisible to the immune system then you could have even better responses. With oncolytic viruses, the treatment can amplify inside the body. This is such a powerful feature of the. The problem is that the immune system is always trying to fight the virus. Getting the virus to the tumor without detection would seem a great strategy.
One company is working on this https://jitc.biomedcentral.com/articles/10.1186/s40425-017-0277-7 https://clinicaltrials.gov/ct2/show/NCT02636036
Other routes that could be investigated further are locoregional (e.g., via the hepatic vein), intrapleural and inhalation https://www.spandidos-publications.com/ijo/31/5/1009 https://www.ncbi.nlm.nih.gov/pubmed/8275514 https://link.springer.com/article/10.1007%2Fs00109-010-0605-6
critic, I read through the triple combo mouse study. This is very impressive! It is quite remarkable that we have now reached an era in which curative responses might occur if patients simply used existing treatment options. For example, Tvec, anti-CTLA4 and anti-PD1 treatments are now already marketed! I am also interested in how additional products in the pipe might combine. For example, NKTR-214 certainly springs to mind. I will be so relieved when cancer is finally a distant memory.
critic, what do you think of the idea of metronomic dosing? Many on this forum are excited by this! It is a simple idea though it could be very powerful! Even something as simple as turning on a pump and doing 24/7 dosing with vitamin C could give very large results. The big concern would be that TLS could occur. Shutting off the energy supply of cancer for a prolonged time should lead to a profound energy crisis for the tumor but not normal cells.
hmm, I had wondered about the anti-body angle of oncolytic viruses. If anti-bodies engage the viruses then what is the point of continuing treatment? Recent research has found this line of thought not to be true.
The abstract for DNX-2401 plus Pembro (NCT02798406) has been published https://academic.oup.com/neuro-oncology/article-abstract/20/suppl_6/vi6/5153658 and the company are running another PhI (NCT03714334) in Spain testing DNX-2440 (this is 'armed' with OX40L).
It would be nice to see more investigator sponsored trials using this in certain indications. Personally, I think another trial in mPDAs should test gemcitabine, nab-paclitaxel and the virus https://www.nature.com/articles/bjc2013415 https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-016-1037-z If that was safe and showed encouraging signs of activity, then they could move things forward by adding on PEGPH20 https://www.cell.com/cancer-cell/fulltext/S1535-6108(12)00039-6 Upon progression they could be then treated with Opdivo (+/- Yervoy).
I'd follow the Drs. Cameron and Pauling trials and then add on a liposomal version as well as powder https://www.isom.ca/article/vitamin-c-cancer-use-oral-vitamin-c/
The (SITC) PR from Replimune https://www.globenewswire.com/news-release/2019/11/08/1943979/0/en/Replimune-Presents-Initial-Clinical-Data-with-RP1-that-Strongly-Supports-Expansion-of-Clinical-Programs-in-Melanoma-and-Cutaneous-Squamous-Cell-Carcinoma-CSCC.html
Poster https://ir.replimune.com/static-files/d8fe8ff4-47ce-4b49-9cea-118b347d79ae
CSCC deck https://ir.replimune.com/static-files/6055ead4-f9f7-496d-bfd5-c2e22b31bd2a
Melanoma deck https://ir.replimune.com/static-files/22e528d6-c3ae-4156-a8db-e8873d9123a4
Event deck https://ir.replimune.com/static-files/9f8d4d33-ef0a-433f-8483-bba680aae25d
A phase I/II study combining a TMZ-CD40L/4-1BBL-armed oncolytic adenovirus and nab-paclitaxel/gemcitabine chemotherapy in advanced pancreatic cancer: An interim report
Background:
Pancreatic ductal adenocarcinoma (PDAC) has been highly resistant to immunotherapeutics to date. LOAd703, an oncolytic adenovirus with transgenes encoding TMZ-CD40L and 4-1BBL, has been shown to lyse tumor cells selectively, induce anti-tumor cytotoxic T-cell responses, reduce myeloid-derived suppressor cell (MDSC) infiltration, and induce tumor regression in preclinical studies.
Methods:
In this phase I/II trial, patients with unresectable or metastatic PDAC are treated with LOAd703 intratumoral injections and standard nab-paclitaxel/gemcitabine (nab-P/G) chemotherapy. Starting on cycle 1 day 15 of nab-P/G, LOAd703 is injected with image guidance into the primary pancreatic tumor or a metastasis every 2 weeks for 6 injections. In the event of sustained tumor control, subjects are eligible to receive 6 more injections. Three dose levels of LOAd703 are being investigated using a BOIN dose escalation design. Primary endpoints are safety and feasibility. Secondary endpoints include response rate and overall survival.
Results:
To date, 13 subjects are evaluable for safety and feasibility. Three patients were treated at dose 1 (5x10e10 VP), 4 subjects at dose 2 (1x10e11 VP), and 6 subjects at dose 3 (5x10e11 VP). The most common adverse events (AEs) attributed to LOAd703 have been fever, chills, nausea, and increased transaminases. AEs have been transient and grade 1-2, with the exception of a grade 3 transaminase elevation in 1 subject receiving dose 3 (the only dose-limiting toxicity observed thus far). During protocol treatment, circulating MDSCs decreased in 8/13 subjects while effector memory T-cells increased in 10/13. ELISPOT analyses showed a rise in tumor antigen-specific T-cells in 10/13 subjects. At the lowest dose level, best response was stable disease, and 6/10 patients who received higher LOAd703 doses have had partial responses. Only 1 patient has had progressive disease as best response.
Conclusions:
Adding LOAd703 to nab-P/G has been safe and feasible. Treatment-emergent immune responses have been demonstrated in most subjects, with a notable proportion having objective anti-tumor responses. Clinical trial information: NCT02705196
T-VEC plus Keytruda (both approved) in STS https://www.cancernetwork.com/news/treatment-combination-may-be-effective-antitumor-activity-advanced-sarcoma
RP2 is 'armed' with GALV-GP-R-, GM-CSF and an anti-CTLA-4 antibody and will be tested both as a monotherapy and with Opdivo (an anti-PD-1 drug) https://clinicaltrials.gov/ct2/show/NCT04336241
Another trial testing RP1 in transplant patients with advanced cutaneous squamous cell carcinoma https://clinicaltrials.gov/ct2/show/NCT04349436
Additional data on LOAd703 could be presented at ASCO and trials are recruiting in pancreatic [1], melanoma [2], and there is a basket as well (pancreatic, ovarian, biliary and colorectal) [3].
Refs:
1 https://clinicaltrials.gov/ct2/show/NCT02705196
Hello, has anyone from the forum been treated at Dr. Arno Thaller's clinic or do you have a referral from someone who has been treated there?
@marcosbomber901 Hi Marcos, I can connect you with a friend that goes there. I will send you now an e-mail with his contact details. Kind regards, Daniel
Oncolytic viruses are moving through clinical trials! This is very exciting! We should assemble the background information here so that D might see the wisdom in writing up a full article on the subject.
I am becoming very positive on OVs, as they can be designed to be extremely cancer specific. Almost any treatment that can be highly cancer specific should be considered carefully as often they can demonstrate substantial efficacy.
There is now a growing and lengthening list of these OVs: T-Vex, Pega-Vec, Telomelysin, HC-101, PVSRIPO, G47 Delta ... . Genetically restricting replication specifically in cancer cells greatly reduces concerns about side effects.
My realization recently that metabolic approaches might magnify the therapeutic effects have increased my excitement level about this approach. One could imagine wave after wave of treatments with these oncolytic virus combined with metabolic stressors (in addition to other combinations including immunological and others). This could become the new paradigm of 21st Century cancer management.
Notably metabolics could play a pivotal role in such a vision of the future. Viruses can be viewed from the perspective of machines consuming vast metabolic resources from the cancer cell-- they need DNA, they need nucleotides, they need surface glycoproteins, ... They consume a huge amount of scarce metabolic resources. Basically, they can be seen as even more voracious parasites than even the cancer cells. Adding in more metabolic stress would simply add yet more burden to the cancer. There is extraordinary potential for this approach.
There are various flavors of OV treatment that have yet to have been explored. For example, one flavor treatment that could be considered is a non-oncolytic viral approach. Instead of directly trying to destroy cancer, one could simply think about infecting and controlling the cancer cells near the nutrient supply. Controlling the high ground would then allow you leverage over the entire rest of the tumor mass.
Perhaps the OVs could be thought of more as a pro-drug, in which they would have built in controls that would need to be activated by additional treatment. With this approach, you could have acquire control over the metabolic behavior of the viruses and thus the cancer cells. For instance, with the virus resident in cancer cells one could treatment a patient with an activator drug which would then turn on the viral replication making machine. Such precise control over the viruses behavior would also give precise control over the cancer cells behavior. This aspect of control is largely lost when oncolysis is placed front and center.
I have attached a spreadsheet of all clinical trials on clinical trials.gov with search term "oncolytic virus". Being able to see all the trials in one place and sort them by study phase, number of patients etc. is a very powerful way to have a broad view of the overall landscape.
Notably there are other viruses that are not included here (e.g., Rigvir and G47 delta). Please feel to upload and add a new sheet to the spreadsheet and then resubmit it. This could be a collective project that we can all build together. It is also interesting to note that from a metabolic perspective treatment efficacy might be defined more as it relates to consuming metabolic resources than as a monotherapy oncolytic agent. Simply proving that an oncolytic virus could selectively replicate in cancer cells and that it metabolically stressed cancer cells would be a valuable addition to the metabolic toolkit. Proving that an OV could do this would also be much easier than trying to establish monotherapy efficacy. If this conception of OVs could be embraced then a greatly accelerated path to approval and to helping patients could occur.
Let's do the background research on this topic so that D can put it all together for us.
Feels good to be right near the research frontier on the metabolic implications of oncotherapy. This one treated with Newcastle and 2-DG; 100% reduction in tumor growth. Somewhat disappointed that incrementally that 2-DG did not seem to add that much, though clearly oncolytic treatment has much to offer, and one could well imagine that more vigorous 2-DG treatment (e.g., metronomic vs. once daily dosing as used in the study, OXHPOS inhibition etc.) would magnify the tumor response. Fairly, impressive that tumor growth was completely stopped with this combination.
https://pubmed.ncbi.nlm.nih.gov/31612140/
This article considers more thoroughly the potential for combining metabolics and onocolytics. The potential to specifically infect tumor cells and then begin dismantling the cancer cells metabolic machinery clearly would be an extremely powerful treatment. For instance, one might begin with a first round oncolytic virus that turned off the pyruvate to lactate short turn (genetic material of the virus might express mirRNA, or shRNA etc. to achieve this). Simply turning off the lactate overproduction should have a large effect. Reasonably, the strategy to pursue would be to normalize the cancer cell's biology. Perhaps doing this could transform the cancer into a normal cell ( I think some research might actually have achieved this). It seems clear that oncolytic therapy will offer us very cancer specific treatments (therefore very safe) which will then allow us to use the metabolic tool set that we are already highly familiar to achieve very large anti-cancer effects. Oncotherapy will be the frontline (perhaps replacing chemotherapy) and then the metabolic combination will create profound anti-cancer responses (as we have seen with combination chemotherapy and metronomic metabolic treatments).
Preliminary results (of RP1) from the 30-subject non-melanoma skin cancers cohort was positive. At the data cutoff, the response rate (in those with cutaneous squamous cell carcinoma) was 86% (n=6/7) including a 57% (n=4/7) complete response rate [1]. In anti-PD-1 refractory melanoma the minimum final objective response rate will be at least 31% [2].
Also, preclinical data [3] and another slightly older paper using T-VEC [4].
Refs (for the trials)
1 https://clinicaltrials.gov/ct2/show/NCT04050436
2 https://clinicaltrials.gov/ct2/show/NCT03767348
@jcancom AstraZeneca is testing an 'armed' NDV https://cancerres.aacrjournals.org/content/77/13_Supplement/4556 https://cancerres.aacrjournals.org/content/79/13_Supplement/1456 https://clinicaltrials.gov/ct2/show/NCT03889275
Another trial testing a genetically engineered HSV-1 that is 'armed' with IL-12, CCL4, FLT3LG, anti-CTLA-4 and anti-PD-1 https://clinicaltrials.gov/ct2/show/NCT04348916
The overall response rate (patients with cutaneous squamous cell carcinoma with at least eight weeks of follow-up) for RP1 plus cemiplimab has increased to 87.5% and the complete response rate is up as well (62.5%).
Also, some early data from the ongoing RP2 (+/- opdivo) trial. Of the six treated (single-agent only), three (50%) have ongoing partial responses. These are in uveal melanoma (prior ipilumumab/nivolumab; extensive liver metastases), mucoepidermoid carcinoma (prior carboplatin/paclitaxel, bicalutamide, ceralasertib), and esophageal (prior durvalumab, M6620, capecitabine, oxaliplatin, cisplatin, chemoradiation; liver and abdominal node metastases). Grade 1-2 (mild and/or moderate) adverse events, including febrile and other constitutional symptoms, local inflammation, and erythema have been observed so far.
Daiichi Sankyo has submitted an IND https://www.onclive.com/view/japanese-approval-sought-for-oncolytic-virus-teserpaturev-for-malignant-glioma
Also, Replimune has dosed the first patient with RP3 https://www.globenewswire.com/fr/news-release/2021/01/05/2153436/0/en/Replimune-Announces-First-Patient-Dosed-with-RP3-in-a-Phase-1-Clinical-Trial-in-Patients-with-Advanced-Solid-Tumors.html
Replimune have provided an update. For the CERPASS trial (RP1 plus libtayo in advanced cutaneous squamous cell carcinoma), at current data cutoff (n=15), seven out of nine responses are complete responses (absence of all detectable cancer), with the current CR rate of 46.6% and overall response rate (CRs plus PRs) of 60%. The company said that a potentially eighth complete response requires biopsy confirmation. This is a registration directed trial, that will initially readout next year, and depending on the data, they could file for approval with the FDA.
For the IGNYTE trial (RP1 plus opdivo), at current data cutoff (n=30), the overall response rate for anti-PD1 naïve melanoma is now 62.5% (50% at SITC, last Nov). The ORR for anti-PD1 failed melanoma remains at 31.25%.
As for RP2 (n=9), as a single agent, there is an ongoing CR (at 15 months for a patient with mucoepidermoid), an ongoing PR (at 18 months for a patient with esophageal), a uveal melanoma patient (who originally had a PR) progressed at 15 months, and an MSS CRC patient with a mixed response in their liver lesions (some reductions) progressed at 6 months.
In the combo trial (RP2 plus opdivo), 27 patients of the planned 30 have been enrolled. Both agents have been well tolerated, with no new safety signals, and 14 have either responded or still have the opportunity for a response.
