INTRODUCTION
As an immunotherapy drug candidate, INKmune seems by far the most commercially sustainable, undervalued that I am aware of. It has the advantages of a CAR-NK based therapy without its limitations, comes with huge cost reduction and scalability potential, and hence risks to marginalize many of its competitors.
How I have come to write the above will be set out below and in the upcoming blog post. As these blog posts are intended for a wider audience, they will elaborate on the larger framework of the immuno-oncology space.
CANCER AS AN IMMUNOLOGICAL DISEASE
Cancer is the second leading cause of death in the United States. Cancer is a disease of immune dysfunction, namely the result of the ineffectiveness of the immune system to fight off cancerous cells that it had otherwise been able to fight off. Cancer and the immune cells in the tumor microenvironment contribute to chronic inflammation, which at its turn propagates tumor growth and survival. Whereas an adequate immune response would have been able to recognize and kill a cancer cell before it could spread and proliferate, it is the lack of such response that contributes to the growth and propagation of a tumor.
The immune system relies on three pillars: (i) detection of ‘non-self’ antigens, (ii) targeting and destroying the malignant cells and (iii) development of immunological memory.
Traditional treatments encompass surgery, chemotherapy, radiation, and bone marrow transplant for hematological malignancies. The downsides to all of those are well-known and are not repeated here.
Even though there is a wide range of cancers and cancer cells, all of the hallmarks of cancer are immune-related (L. S. Milane, ‘The hallmarks of cancer and immunology’, in M. M. Amiji and L. S. Milane (ed.), Cancer Immunology and Immunotherapy, Elsevier, 2022).
Cancer is essentially a disease of the failing immune system. In the current age of immunology, novel discoveries and advances in immunotherapies are seeing the light of day, and immuno-oncology is therefore likely to change the field forever. This field encompasses monoclonal or bispecific antibodies targeting tumor antigens, immune checkpoint inhibitors that inhibit proteins (checkpoints) that prevent activation of the immune cell, cancer vaccines, and adoptive cell therapies. Each of these therapies is considered to have its advantages and limitations.
One will already note that pseudokines™ are not part of the existing range of therapies.
ADOPTIVE CELL THERAPIES: THE SHIFT FROM T-CELLS TO NK-CELLS
Adoptive cell therapies, whereby specific cells of the immune system are given to the patient to help the immune system fight cancer, are the most promising therapies of those mentioned above.
The focus of drug development in adoptive cell therapy has originally been mostly on T-cells, immune cells which are part of the adaptive immune system and which are more abundantly present than NK cells.
In the few adoptive cell therapies that have been approved over the course of the past ten years, immune cells are taken from the patient's own blood or tumor tissue (autologous, meaning ‘from the body itself’), proliferated, engineered, and then reinserted into the patient.
The engineering technique often used is called CAR (Chimeric Antigen Receptor), expressing an add-on to an immune cell which allows the immune cell to, e.g., bind more easily to an antigen on a tumor-cell and/or to target and kill a tumor cell that had up to then evaded the immune system.
To produce a CAR immune cell, cells are isolate and purified from the patient blood, cryopreserved, transported to the designated center, thawed, enriched, activated by use of monoclonal antibodies resulting in proliferation, and then engineered to include a CAR targeting a tumor-associated target antigen. This is an extremely complex process.
First-generation T-cells have been successful, yet to a limited extent, meaning there is a need for improvement of efficacy and potency of these therapies. The field of trials and drug development is continuously evolving, with meanwhile four generations of CARs which become always more complex, and further developments such as so-called Armored CAR’s, Split Receptor CAR’s, Off-Switch CAR’s, Tagged CAR’s, Dual CAR’s, TanCAR’s and iCARs.
As CAR-engineered cells are antigen-specific, they can only target and kill tumor cells who possess the specific antigen for which the CAR-T-cell has been engineered. The engineering of those cells becomes all the more complex, leading to additional manufacturing costs.
CAR-T-cell therapies also come with a problem of toxicity in that they produce cytokines and may lead to cytokine-release-syndrome.
Finally, many CAR-T based therapies have also reported a problem of persistency, meaning the effect of the therapy does not last long, and additional infusions of CAR-T cells would need to be administered.
THE SHIFT TO NK -CELLS
The focus of adoptive cell therapy is now shifting, or at least broadening to NK-cells, or natural killer cells. Despite being less present than T-cells, the NK cells are the most effective killer cells in the human body, and they carry out essential roles of immune surveillance. They were traditionally considered not to have immunological memory, contrary to T-cells, but this has been proven incorrect in recent years.
THE COMPETITIVE FIELD
CAR-T and CAR-NK cell therapy development is going through a meteoric rise.
The field is being driven here by companies such as Kite Therapeutics, Abbvie, Takeda Pharmaceuticals, Fate Therapeutics, Century Therapeutics, but many other names such as Adaptimmune, Agios, Allogene, Amgen, Anixa, Autolus, Bluebird Bio, Celgene, Cellectis, Celyad, Crispr, Gilead, Hoffmann-La Roche, Immune Cell, IN8 Bio, Janssen, Juno Therapeutics (bought for $9 billion by Celgene), Mustang Bio (part of Fortress Bio), Nektar Bio, Novartis, Pfizer, Servier, Sorrento, Timmune, just to name a few, are also active in the field.
However, to my knowledge, none of all of the therapies being developed by the afore-mentioned or other companies in the T- or NK-cell space use a pseudokine™, and all of them face the same issue; the engineered cells are becoming more and more complex, and the resulting cost of manufacturing is prone to go up.
There are about 60 trials recruiting related to NK cells, of which 16 are autologous, 39 are allogeneic, and 9 are related to umbilical cord blood NK cell-related, and some of which also related to memory-like NK cells.
HEMATOLOGICAL VERSUS SOLID TUMORS
Historically, CAR-T cell therapy has been more successful against hematological malignancies as compared to against solid tumors. The tumor microenvironment in solid tumors, which is highly immunosuppressive, is entirely different. There may be a higher rate of antigen heterogeneity. And there may be on-target/off-tumor toxicity, when CARs are attacking essential organ tissue instead of just the solid tumor.
AUTOLOGOUS VERSUS ALLOGENEIC THERAPIES
The existing CAR-T immunotherapies are autologous, which means T-cells are taken from the body, engineered in laboratories, to then subsequently be reinserted into the body. That process is complex. The future is therefore allogeneic, or off-the-shelf. At this point of the state of science, when one says allogeneic in these kinds of therapies, one thinks of immune cells that do not originate from the sick patient himself, but come from an external donor, to then be proliferated and engineered in laboratories. At this point, one does not automatically think of a fully external cell line such as the one INKmune is.
FREEZE/THAW TEMPERATURE CONCERNS
The current immunotherapies require T- or NK-cells to be frozen at -150° C. This makes storage, transportation and administering complex, as freezers that offer these temperatures are rare, and patients will need to go to hospital to be dosed.
Regular pharmacies don’t have such freezers, but do have freezers that can store at -80° C. For instance, Covid vaccines are to be stored at -80° C.
CAR-T CELL THERAPY VERSUS CAR-NK CELL THERAPY
The advantages of CAR cell therapy have made them more promising than any other immune therapy. Even though most work has been performed on CAR-T cells, the current focus is more on CAR-NK cell therapies.
However, essential limitations of CAR-T cell based therapies are:
- Persistency; patients who have been in remission eventually often relapse due to lack of persistency of the therapy leading to antigen loss or tumor escape; there have been efforts to solve this (e.g. further engineered CAR’s or preconditioning of patients with chemotherapy) which however also come with side effects such as toxicity;
- Limitation of target antigens; CAR-T’s can only bind to and kill those antigens for which they have been engineered;
- Toxicity concerns including on-target/off-tumor toxicity; CAR T-cell therapy is considered a double edged-sword as activation of T-cells often leads to release of cytokines, resulting in cytokine-release syndrome, graft-versus-host-disease, macrophage activation syndrome or neurological toxicities;
- Hematological versus solid tumors; ‘homing’ of infused CAR-T cells inside the tumor is very challenging, and the immunosuppressive environment of the tumor with lack of nutrients, oxidative stress, hypoxic conditions and acidic pH is a further inhibitor of successful treatment.
CAR-NK based therapies essentially follow the same engineering mechanism of CAR-T based therapies, and they are having the same evolution with ever more complex designs. However, they do not come with the toxicity issue CAR T-cell trials are facing, and the trials so far do not seem to bring any major adverse effects.
CAR-NK cell therapies are also mostly directed at hematological malignancies, and very few trials are being conducted against solid tumors. The ongoing clinical trials are still in early phases, where safety, pharmacokinetics and dosage are being evaluated.
The advantages of CAR-NK cell based therapies are:
- they are safer than T-cell treatments; there is no toxicity nor graft-versus-host disease;
The majority of current clinical trials with CAR-NK cells use the NK92 cell line because of its unlimited proliferation ability in vitro and likely reduced sensitivity to repeated freeze/thaw cycles.
The limitations of CAR-NK based therapies are:
- the complex design of CARs;
- NK cells have a low persistence in vivo;
- difficulty to penetrate into the tumor bed of a solid tumor due to some of the immunosuppressive factors thereof;
- freeze/thaw issues that may decrease the percentage of live CAR transduced NK cells and hence functionality.
COSTS, SCALING UP AND COMMERCIAL VIABILITY
As of April 2021, five commercially available chimeric antigen receptor (CAR) T cell therapies for hematologic malignancies have been approved. Many more are expected to be approved in the years to come, both in hematological malignancies as in solid tumors. By 2026, commercial CAR T cell therapies are expected to comprise the largest share of oncology drug sales in pediatric and young adult patients with acute lymphocytic leukemia (ALL; 44%) and adults with diffuse large B-cell lymphoma (46%).
The cost of immunotherapy ranges from 70,000 USD to pretty much $1,000,000, which is extremely expensive and simply unaffordable for the masses. In April 2021, a study had found that the cost of CAR-T therapy is $ 373,000, the total cost averages more than $700,000 and can exceed $1 million in some cases. It has been reported in November 2021 that although the median drug cost alone was $411,278, the median total cost of care for CAR-T therapy was $610,999 and in 12% of cases, the total cost of care exceeded $1 million.
Even with the price of such therapies being cut in half or more, immunotherapy based on the engineering of T-cells is for the happy few, and can never be applied to the general public. An average household simply does not have that amount of money. And social security systems in Europe would not be able to support these kinds of costs on a larger scale.
Then there is the question of scalability, which investors may tend to forget. Already now, with these therapies not being available to a wide public yet, there have been manufacturing delays and problems with meeting target doses in commercial production. The complex manufacturing process, including cryopreservation, transportation, thawing, enriching, proliferating and engineering, also includes safety testing. The use of specific bioreactors or other cell culture devices for all of these processes requires trained staff and stringent cleanroom environments, making them less desirable for commercial CAR T cell manufacturing intended for a large number of patients.
However, insofar as I am aware, none of all of the therapies being developed by the afore-mentioned or other companies in the T- or NK-cell space use a pseudokine™ and all of them face the same issue; the engineered cells are becoming more and more complex, and hence the cost of manufacturing is unlikely to go down. Just saying: the immuno-oncology space is red-hot, and INmune Bio’s product is unique.
The conclusion is, to me, that there are many drug candidates out there that may in theory be able to help the massive need for tumor treatment, but that the average patient simply won’t be able to afford. There will be, and will have been, many conversations between doctors and sick patients, where the conclusion will be or will have been: the possibly life-extending treatment may exist, but if already it would work in the concerned patient, it is so costly that the patient cannot or does not want to afford it.
NK CELL ACTIVATION THRESHOLD AS AN ESSENTIAL PART OF THE SCIENCE UNDERLYING TO INKMUNE
As mentioned, NK cells carry out an essential function of immune surveillance in the body.
The essential underlying science to INKmune, as originally reported by among others Prof. Lowdell of INmune Bio in 2002 and with more specificity in 2019, is that a patient’s NK cells’ activation level – or ‘cytotoxicity’ – is a predictor of overall survival. What has been shown is that, in patients with NK cytotoxicity above a certain threshold, there is substantially higher (9 in 11) overall survival (OS) over the course of two years, whereas in patients with NK cell activation below that level, there is a substantially higher (7 out of 8) death rate over the same period.
In other words, if the level of activation of a patient’s NK cells is above a certain threshold, these patients are likely to survive over a prolonged period of time, whereas if that is not the case, these patients are likely to die over that same period.
What seems to matter for prolonged survival of patients, then, is the threshold of activation of one’s NK cells. And that threshold seems to be 20,85%.
If one, then, can ‘prime’ the existing NK cells to a higher level of activation, or even from a level below the threshold to one above the threshold, such priming is likely to substantially improve a patients’ overall survival, merely by boosting a patient’s own immune system.
If applied in combination with other therapies, this therapy is likely to yield even better results.
To be clear, the NK cell activation levels in these patients is far below the average of a healthy person’s.
One then understands that the results in the first patient on INKmune whose NK cells’ activity had gone up from <15% to +70% at day 29, which is about a 400% increase in NK level activity and far above the above threshold of 20.85%, with this activity remaining at elevated levels (60%) up to day 119, is fantastic. For the record, the patient had only been given three rather low doses only over an initial period of 14 days.
INKMUNE MAY OUTPERFORM THE REST
The mechanism of action of INKmune is as follows.
INKmune is a ‘pseudokine’™.
INKmune™ binds to multiple NK ligands and initiates the activation of over 3,000 genes associated with function, trafficking, proliferation, and survival to form memory-like NK cells, which have superior cancer killing function. In our hands, no single cytokine has such broad physiological effects on NK cells compared to INKmune-primed NK cells, and this has inspired us to refer to INKmune™ as a pseudokine.”
INKmune is an NK-cell based program. It comes with the advantages of NK-cell based therapies, but does not come with the limitations of T-cell therapies.
INKmune therapy has shown no symptoms of cytokine-release syndrome or toxicity. INKmune does not come with a toxicity problem. It is safe, and no adverse effects at all have so far been noted, nor would they have been expected.
INKmune is persistent and generates memory-like NK cells, that aspect is hot these days, and is certain to generate attention from the scientific community. In fact, INKmune’s persistence in vivo so far has even outperformed INmune Bio's expectations.
It is an allogeneic/off-the-shelf drug candidate, not an autologous one, and hence does not come with the typical downside relating to autologous therapies.
INKmune does not require engineering of cells, and does not come with all the complex, timely and costly processes that that entails. It is not a CAR-based therapy or anything of the sort. INKmune is an existing cell line that has been proliferated in the lab. It is much easier to manufacture than any of the existing therapies.
It is not antigen-specific, contrary to all existing therapies or those in development, meaning it can kill multiple tumor cell lines that had up to then evaded the immune system.
In vitro, INKmune showed good results in both hematological as in solid tumors as well, and the INKroc trial in ovarian cancer (same drug) will soon start.
Production of INKmune is much easier than the CAR-T and CAR-NK cell therapies that are currently being developed, to my knowledge.
As production of INKmune should come with a huge cost reduction compared to the above therapies, this form of immunotherapy should no longer be for those who can afford it.
There should be no problem of scalability.
INKmune can be stored at -80° C instead of – 150° C, which again allows for much more easy marketing. It could even be made available in regular pharmacies, so there would be no need to visit the hospital.
Although it is early-stage, the current results in hematological malignancies are simply outstanding.
INmune Bio holds exclusive rights to the patent related to the method of in vivo priming of natural killer cells, with patent life extending until 2036. For me, that means it holds proprietary rights to the new chapter in the upcoming immuno-oncology handbooks. And I expect more than one player to want to acquire those rights.
The NK and immuno-oncology space is red hot, and the FDA has a positive attitude with regards to approval of these therapies, with further approvals expected in the years to come. Many big pharma players have included CAR- and/or NK-cell based programs in their drug development pipeline. With cancer as second leading cause of death and billions of dollars at play, upcoming results of INKmune in both hematological and solid tumors will almost certainly generate interest of larger players.
The price tag question is essential too here. INKmune can be manufacturated for far less than existing immunotherapies and those in development, meaning it could be opened up to the general public, and social security systems may be able to support its costs on a large scale. INKmune’s manufacturing is easy and scalability does not appear to be of any concern. There is need for many of the processes needed for existing immunotherapies or those in development. This is probably the aspect that will be of interest to big pharma most of all.
CONCLUSION
For all of the above facts and considerations, I consider INKmune by far the most commercially sustainable, undervalued, paradigm-shifting drug candidate among the immunotherapy drug candidates that I am aware of.
It has the advantages of a CAR-NK based therapy without its limitations, comes with huge cost reduction and scalability potential.
It risks to outperform many of the existing drug candidates, or those in development, by far.
I believe the market has not understood where INKmune stands in the immuno-oncology space, and that it considers it to be just another NK-cell based program, without noticing that it comes with unseen advantages, including some that are of high commercial relevance.
It seems inevitable to me that with time, and with the results this program should yield, the market, the scientific community, competitors and big pharma pick up on this sooner or later. Add to this, the limitless and multi-billion dollar potential of XPro, as explained in the previous blog posts [1] and [2].
Therein lies the extremely promising investment opportunity in INmune Bio, in my eyes, and the reason why I wanted to create this website. However, don't take this as investment advice, as indicated in the about section to this website.
I intend to take a closer look at the exact working of INKmune, the results it has yielded so far, and how I see its future, in the upcoming blog post.
Great writeup!