StemVacs-P iPSC

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TimGDixon
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StemVacs-P iPSC

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Treatment of Parkinson’s Disease by Immune Modulation and Regenerative Means
Disclosed are means, methods and compositions of matter for treatment of Parkinson’s Disease through concurrent immune modulation and regenerative means. In one embodiment Parkinson’s Disease is treated by augmentation of T regulatory cell numbers and/or activity while concurrently providing regenerative cells such as mesenchymal stem cells, and/or dopamine secreting cells. In one embodiment administration of immunoglobulins such as IVIG together with low dose interleukin-2 and/or low dose naltrexone is disclosed as a preparatory means prior to administration of therapeutic cells such as stem cells. Other therapeutic means utilized in an adjuvant manner are also provided for hormonal rebalancing, transcranial magnetic stimulation, and deep brain stimulation.

Parkinson’s Disease (PD) is believed to be the second most common and fastest growing neurodegenerative disorder worldwide. At present, it affects 2–3% of individuals over the age of 65, which is expected to double by the year 2040 [1, 2]. PD presents with motor symptoms such as tremors and bradykinesia, and non-motor symptoms, such as disordered sleep and cognitive dysfunction. As there is no cure for PD, symptoms inevitably progress and inflict devastating consequences on individuals and on their families [3-5]. In common with Alzheimer and other neurodegenerative diseases, PD is biologically characterized by protein misfolding and the rampant death of neurons [5-9]. Specifically, PD is characterized by the aggregation of α-synuclein protein and the death of dopaminergic neurons in the midbrain substantia nigra (SN), although PD affects other neurotransmitter systems as well [10-15]. Neuroinflammation has been associated with PD both in animal models [16-19], and in autopsy samples of patients [20, 21].

The medical treatment of Parkinson's disease is directed to stopping, slowing down, reducing the extent of or minimizing the neurodegenerative process in nigrostriatal neurons (neuroprotective therapy) and eliminating the biochemical imbalance (symptomatic therapy). The main directions of symptomatic therapy in Parkinson's disease are to increase dopamine synthesis, or stimulate dopamine receptors activity and dopamine release from the presynaptic space, and to inhibit dopamine reuptake by presynaptic receptors and dopamine catabolism.

The gold standard in the pharmacological treatment of Parkinson's disease is provided by DOPA-containing substances such as levodopa. Levodopa is commonly administered in combination with carbidopa, which increases the half-life of levodopa. However, the efficacy of these agents decreases over time because of continuing degeneration of neurons in the substantia nigra.

Example
Decrease in Substantia Nigra Inflammation by Tol-DC and Preservation of Dopaminergic Neurons
Tol-DC (StemVacs) was generated by culture of umbilical cord adherent monocytes in GM-CSF 10 ng/ml and IL-4 (5 ng/ml) for 7 days. Cells were treated with 5 ng/ml IL-10 to generate (Tol-DC), whereas conventional DC were cells grown under identical conditions with no IL-10.

The cells were transferred i.v. at one and two weeks prior to intoxication with four 16 mg/kg doses of MPTP. Mice treated with PBS or MPTP alone served as controls. Two days after MPTP intoxication, mice were sacrificed, brains removed, frozen, and cryosectioned at 30 μm/section through the midbrain containing the substantia nigra. Sections were stained for Mac-1 expression by microglia.

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1. Poewe, W., et al., Parkinson disease. Nat Rev Dis Primers, 2017. 3: p. 17013.
2. Dorsey, E.R. and B.R. Bloem, The Parkinson Pandemic-A Call to Action. JAMA Neurol, 2018. 75(1): p. 9-10.
3. Armstrong, M.J. and M.S. Okun, Diagnosis and Treatment of Parkinson Disease: A Review. JAMA, 2020. 323(6): p. 548-560.
4. Reich, S.G. and J.M. Savitt, Parkinson's Disease. Med Clin North Am, 2019. 103(2): p. 337-350.
5. Baumann, C.R., et al., Body side and predominant motor features at the onset of Parkinson's disease are linked to motor and nonmotor progression. Mov Disord, 2014. 29(2): p. 207-13.
6. Kaur, R., S. Mehan, and S. Singh, Understanding multifactorial architecture of Parkinson's disease: pathophysiology to management. Neurol Sci, 2019. 40(1): p. 13-23.
7. Majd, S., J.H. Power, and H.J. Grantham, Neuronal response in Alzheimer's and Parkinson's disease: the effect of toxic proteins on intracellular pathways. BMC Neurosci, 2015. 16: p. 69.
8. Hinault, M.P., A. Farina-Henriquez-Cuendet, and P. Goloubinoff, Molecular chaperones and associated cellular clearance mechanisms against toxic protein conformers in Parkinson's disease. Neurodegener Dis, 2011. 8(6): p. 397-412.
9. Dong, Z., et al., Hsp70 gene transfer by adeno-associated virus inhibits MPTP-induced nigrostriatal degeneration in the mouse model of Parkinson disease. Mol Ther, 2005. 11(1): p. 80-8.
10. Teil, M., et al., Targeting alpha-synuclein for PD Therapeutics: A Pursuit on All Fronts. Biomolecules, 2020. 10(3).
11. O'Hara, D.M., S.K. Kalia, and L.V. Kalia, Methods for detecting toxic alpha-synuclein species as a biomarker for Parkinson's disease. Crit Rev Clin Lab Sci, 2020: p. 1-17.
12. Bernal-Conde, L.D., et al., Alpha-Synuclein Physiology and Pathology: A Perspective on Cellular Structures and Organelles. Front Neurosci, 2019. 13: p. 1399.
14. Koppen, J., et al., Amyloid-Beta Peptides Trigger Aggregation of Alpha-Synuclein In Vitro. Molecules, 2020. 25(3).
15. Faustini, G., et al., Alpha-Synuclein Preserves Mitochondrial Fusion and Function in Neuronal Cells. Oxid Med Cell Longev, 2019. 2019: p. 4246350.
16. Shams, R., N.L. Banik, and A. Haque, Calpain in the cleavage of alpha-synuclein and the pathogenesis of Parkinson's disease. Prog Mol Biol Transl Sci, 2019. 167: p. 107-124.
17. Miller, R.M., et al., Wild-type and mutant alpha-synuclein induce a multi-component gene expression profile consistent with shared pathophysiology in different transgenic mouse models of PD. Exp Neurol, 2007. 204(1): p. 421-32.
18. Smeyne, R.J., et al., Assessment of the Effects of MPTP and Paraquat on Dopaminergic Neurons and Microglia in the Substantia Nigra Pars Compacta of C57BL/6 Mice. PLoS One, 2016. 11(10): p. e0164094.
19. Sherer, T.B., et al., Mechanism of toxicity in rotenone models of Parkinson's disease. J Neurosci, 2003. 23(34): p. 10756-64.
20. Harms, A.S., et al., Delayed dominant-negative TNF gene therapy halts progressive loss of nigral dopaminergic neurons in a rat model of Parkinson's disease. Mol Ther, 2011. 19(1): p. 46-52.
21. Toulorge, D., A.H. Schapira, and R. Hajj, Molecular changes in the postmortem parkinsonian brain. J Neurochem, 2016. 139 Suppl 1: p. 27-58.
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TimGDixon
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Re: StemVacs-P iPSC

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What is MPTP? Known as N-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine it is a close cousin of Ecstasy and many unsuspecting people think they are buying molly or ectstasy (3,4-Methyl​enedioxy​methamphetamine) but in fact are sold MPTP. We use it in animal models because of the rapid onset of the Parkinson's like presentations. You parents and grandparents out there need to caution your children about using these drugs that just like heroin could be fentanyl and kill you quickly, so can MPTP give a 20 year old Parkinson's.

Street-Drug Contaminant causing Parkinsonism
The following information was submitted by the National Institute on Drug Abuse and the National Institute of Mental Health, and has been sent to state alcohol and drug abuse agencies and drug treatment programs.

Recently, a street-drug contaminant has appeared that can cause parkinsonism in drug abusers. The compound N-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) has been identified in underground laboratory preparations of a potent analog of meperidine (Demerol).

Over the past 8 years, sporadic outbreaks of MPTP-induced parkinsonism have occurred among drug abusers in California, Maryland, and Vancouver, British Columbia.

Two different synthetic methods were used by the underground chemists, and, in both instances, MPTP was present as a side product in the final drug preparation used or sold in conjunction with these outbreaks. The MPTP-containing powder, sometimes sold as a new "synthetic heroin," was dissolved in water and administered intravenously or taken by the intranasal route. This contaminant has been documented to produce irreversible chronic parkinson symptoms in drug abusers. Two deaths in Vancouver, British Columbia, have been attributed to use of this drug.

MPTP-induced parkinsonism in man is remarkably similar to idiopathic Parkinson's disease. All the major clinical features of Parkinson's disease are present: generalized slowing and difficulty moving, rigidity, resting tremor, flexed posture, and loss of postural reflexes. In addition, neurochemical abnormalities resembling those seen in patients with Parkinson's disease have been noted. These symptoms and signs subside temporarily after treatment with L-dopa or with bromocriptine, drugs used in treating Parkinson's disease. The neurotoxicity of MPTP has produced a severe, permanent parkinsonian syndrome in a number of drug abusers who continue to require treatment. Based on autopsy findings in one case, MPTP appears to destroy nerve cells in the substantia nigra, an area of the brain that plays a major role in controlling movement.

Since some cases of MPTP-induced parkinsonism have been misdiagnosed as catatonic schizophrenia, careful diagnostic evaluation and appropriate treatment are indicated.

While the instances of MPTP-induced parkinsonism have been limited to relatively few individuals, the possibility of far greater public health impact must be considered, because more drug-abusing individuals than those already identified have probably been exposed, and the effects of the drug appear to be cumulative and may not appear for several years.

Further studies of patients with MPTP-induced parkinsonism are currently under way at the National Institute of Mental Health.

If patients with suspected MPTP-induced parkinsonism are identified or if additional information is needed, contact Dorynne Czechowicz, M.D., Assistant Director for Medical and Clinical Affairs, Division of Prevention and Communications, Alcohol, Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse, at (301) 443-6780.

Disclaimer All MMWR HTML documents published before January 1993 are electronic conversions from ASCII text into HTML. This conversion may have resulted in character translation or format errors in the HTML version. Users should not rely on this HTML document, but are referred to the original MMWR paper copy for the official text, figures, and tables. An original paper copy of this issue can be obtained from the Superintendent of Documents, U.S. Government Printing Office (GPO), Washington, DC 20402-9371; telephone: (202) 512-1800. Contact GPO for current prices.

**Questions or messages regarding errors in formatting should be addressed to mmwrq@cdc.gov.


This 42-year-old man had used a total of 4·5 g of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) over a 4-day period. This video shows footage after his initial admission to hospital in an untreated state (segment 1), and then following treatment with levodopa/carbidopa (segments 2 and 3).


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TimGDixon
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Re: StemVacs-P iPSC

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I forget to talk about additional StemVacs platform immunotherapeutics.

The immune system's natural capacity to detect and destroy abnormal cells may prevent the development of many cancers. However, cancer cells are sometimes able to avoid detection and destruction by the immune system.

Cancer cells may:
  • reduce the expression of tumor antigens on their surface, making it harder for the immune system to detect them
  • express proteins on their surface that induce immune cell inactivation
  • induce cells in the surrounding environment (microenvironment) to release substances that suppress immune responses and promote tumor cell proliferation and survival
In the past few years, the rapidly advancing field of cancer immunology has produced several new methods of treating cancer, called immunotherapies, which increase the strength of immune responses against tumors. Immunotherapies either stimulate the activities of specific components of the immune system or counteract signals produced by cancer cells that suppress immune responses.

The overarching approach to cancer on our StemVacs platform is as follows:
  • Treat innate immune suppression: Administration of oral apigenin/pterostilbene (Cancer Metabolic DeTox Product) to decrease immune suppressive toxic molecules made by tumor and tumor microenvironment.
  • Treat adaptive immune suppression: Administration of MemoryMune to activate dormant memory cells recognizing the tumor. Administration of LymphoBoost to repair deficient IL-12 production.
  • Stimulation of immune response to cancer stem cells (StemVacs).
  • Consolidation and maintenance of immunity: Cycles of StemVacs, supported by innaMune and LymphoBoost
Cancer Metabolic DeTox: This is an orally administered agent that is derived from various herbs termed apigenin. The unique property of apigenin is that it inhibits a cancer associated metabolic pathway that degrades the amino acid tryptophan. Specifically, apigenin inhibits the enzyme indolamine 2,3 deoxygenase (IDO), which is responsible for breaking down tryptophan in the vicinity of the tumor and generating by-products such as kynurenine. It is known that immune activation is dependent on tryptophan being present in the tumor environment. The depletion of tryptophan and generation of kynurenine by tumor cells and tumor associated cells is a major cause of immune suppression in cancer. By administering Cancer Metabolic DeTox, the innate arm of the immune system has a chance to regenerate. This positions the patient for better outcome after administration of specific immune stimulating vaccines.

innaMune: Is a biological product derived from a tissue culture of blood cells derived from healthy donors. It is a combination of cytokines that maintain activity of innate immune system cells, as well as having the ability to shift M2 macrophages to M1. In one instance a composition is extracted from polyvalently activated peripheral blood mononuclear cells through dialysis. This immune modulator is useful for the treatment of cancer and alleviation of cancer associated immune depression. As an immunomodulator, innaMune acts as a costimulatory of T cell activation by modulation of cytokine production. In another application the immune modulator is concentrated for miRNA species capable of activating innate immune cells.

LymphoBoost: Is a proprietary formulation of Mifepristone, a drug approved for another indication, which we have shown to be capable of stimulating lymphocytes, particularly NK cells and T cells, both critical in maintaining anti-tumor immunity. LymphoBoost is useful for improving a treatment outcome and/or an alteration of immunity in a condition that benefits from immune stimulation. In particular, administration of sufficient doses of mifepristone or a derivative, alone, or in combination with an immunotherapeutic such as, but not limited to, an antibody, a vaccine, a cytokine, or a medicament whose therapeutic activity is associated with immune modulation.

MemoryMune: Is a product derived from a two-step culture process of donor blood cells. The product MemoryMune reawakens dormant immune memory cells. It is known that many cancer patients possess memory T cells that enter the tumor, however, once inside the tumor these cells are inactivated. MemoryMune contains a unique combination of growth factors specific for immune system cells called "cytokines".

StemVacs: A platform for antigen-nonspecific immune modulatory treatment that can be utilized as a monotherapy or as a combination with antigen specific modalities such as peptide or protein based vaccines.

Drug Candidate BRS-001: Cancer Stem Cell Targeted Immunotherapy

BRS-001 is a patent-pending cellular immunotherapy developed by scientists at Therapeutic Solutions International, Inc., a San Diego Biotechnology Company, which is available at the Pan Am Cancer Treatment Center in Tijuana Mexico to treat stages 1-4 in breast cancer.

BRS-001 activates the immune system to seek and destroy cancer stem cells, based on their expression of a protein named Brother of the Regulator of Imprinted Sites (BORIS). BRS-001 is generated using white blood cells of the patient, which are grown outside of the body to create dendritic cells. The patient’s own dendritic cells are treated in vitro with peptides derived from BORIS, and subsequently are injected back into the patient in order to program the immune response to kill cells that express the protein BORIS, which are cancer stem cells.

Without Killing of Cancer Stem Cells it is Impossible to Cure Cancer
All tumor cells are the offspring of a single, aberrant cell, but they are not all alike. Only a few retain the capacity of the original cell to create an entire tumor. Such cancer stem cells can migrate to other tissues and become fatal metastases. To fully cure a patient's cancer, it is crucial to find and eliminate all of these cells because any that escape can regenerate the tumor and trigger its spread through the body.

BORIS is Essential for Cancer “To be Cancer”
The BORIS protein functions to disable a tumor suppressor termed “CTCF”[1]. The role of CTCF is to ensure that parts of DNA that should not be activated, indeed are not activated. For example, one of the roles of CTCF is to block expression of genes that cause cancer[2]. In cancer stem cells, BORIS blocks the function of CTCF, thus allowing for propagation of cancer. It has been shown that if BORIS is blocked in cancer stem cells, the cancer stem cells no longer form tumors[3].

BRS-001 is Selective Immunotherapy
Dendritic cells are the most potent immune stimulatory cell of the body. Currently dendritic cell therapy is approved in the USA in the form of the drug Provenge. BRS-001 consists of dendritic cells that are treated with parts of the BORIS protein in order to stimulate killer T cell responses against any cell that expresses BORIS. Using dendritic cells to stimulate immunity offers the advantage of inducing immunological memory against the tumor. Published studies by us in collaboration with the NIH showed immunity to BORIS results in tumor killing[4],[5].

Preclinical Proof
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The BRS-001 construct is capable of stimulating immune responses that cross over to wild-type tumors without having the potential of causing cancer. This ability to induce tumor immunity was validated across a broad variety of tissue types making the BRS-001 approach broadly applicable for numerous cancers. This was described in peer reviewed papers by Company scientists demonstrating that immunization with BRS-001 not only inhibits growth of aggressive breast cancer 4T1 cells in BALB/c mice, but also that mice immunized with BRS-001 contain high numbers of CD8+ T cells that have spontaneous cytolytic activity against breast, leukemia, and glioma cells in vitro.

Company scientists have determined that vaccination with BRS-001 in the context of various immune stimulatory technologies induces a CD8 cytotoxic T cell response that recognizes tumors independent of tissue origin.

1Hong et al. Cancer Res. 2005 Sep 1;65(17):7763-74.
2Fiorentino et al. J Cell Physiol. 2012 Feb;227(2):479-92.
3Alberti et al. PLoS One. 2015 Jul 17;10(7)
4Loukinov et al. J Cell Biochem. 2006 Aug 1;98(5):1037-43.
5Ghochikyan et al. J Immunol. 2007 Jan 1;178(1):566-73.
Rhondap800
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Re: StemVacs-P iPSC

Post by Rhondap800 »

Hey TimGDixon,

Where are these studies published and I was not able to find it.
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TimGDixon
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Re: StemVacs-P iPSC

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Hi Rhonda Do you mean as in the Example of StemVacs-P I posted? That didn't come from a published paper I was just sharing background research we do ahead of filing patents. All patents we file either have preclinical or cell line data or both to support our claims.
Konghusker
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Re: StemVacs-P iPSC

Post by Konghusker »

Where exactly are you on the stemvacs timeframe? What’s the next step and how far out is this roughly for being a realistic treatment for cancer treatments in the US? I know jadicells is the current excitement, but I originally got in for this cancer treatment and am just curious about the process/steps and where it is in the process. It’s what I’m most excited about due to cancer affecting so many people I know. Thanks Tim, and happy thanksgiving.
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TimGDixon
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Re: StemVacs-P iPSC

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Cancer is a long haul and this will be many years. We are currently in IND review with our investigational product known as "StemVacs-V: Interferon Gamma Pretreated Allogeneic iPSC Derived Endothelial Cells" for "Treatment of Metastatic Breast Cancer by StemVacs-V Cancer Immunotherapeutic".

Trial design is based on other Phase I studies utilizing tumor antigens to stimulate immunity towards metastatic disease, in which primary endpoint is demonstration of immunogenicity as well as safety. Additionally, considerations were made in terms of previous studies involving administration of endothelial cells, as well as other anti-angiogenic based immunotherapies.

At present there are no plans for additional clinical investigations of StemVacs-V within the first year of filing the current IND.

Prior animal studies with StemVacs-V have not revealed particular adverse effects.

The proposed study will assess feasibility and safety of an allogeneic therapeutic vaccine, StemVacs-V comprising inducible pluripotent stem cell (iPSC) derived endothelial-like cells generated under conditions designed to replicate the tumor microenvironment. StemVacs-V is designed to replicate tumor endothelial cells and induce immunity

Numerous preclinical studies in animal models, as well as 2 clinical studies, have demonstrated the feasibility of breaking tolerance to tumor associated endothelium, while not inducing cross-immunity towards healthy endothelium. Previous clinical studies have utilized human umbilical vein derived endothelial cells as a polyvalent immunogen, the current approach is modified in that iPSC-derived endothelial cells are utilized.

This modification is performed based on: a) need for consistency of manufacturing; b) significantly higher amount of endothelial cells can be derived from the iPSC source as compared to umbilical cord; and c) ability for future generations of the vaccine to utilize molecular adjuvants. Additionally, the iPSC based StemVacs-V product is different than classical endothelial cell vaccines due to the step of pre-treatment with interferon gamma, which is performed in order to augment immunogenicity of tumor endothelial-like cells.

In the current study we seek to evaluate safety and signals of efficacy of StemVacs-V. Treatment protocol will comprise of 4 administrations of StemVacs-V, once per month, with each administration consisting of 4 separate intradermal administrations of 2.5 million cells in a volume of 1 ml. Therefore total cell dose will be 40 million cells, with 10 million cells administered per month.

Rationale:
Blockade of tumor angiogenesis is a therapeutically attractive target, which has been the basis of several FDA approved drugs such as Avastin. Numerous studies preclinical and clinical studies have demonstrated endothelial derived cells are capable of stimulating immunity towards tumor endothelium. Such an active immunity against polyvalent antigens offers the possibility of superior therapeutic results, with a decreased possibility of acquired resistance. StemVacs-V is an iPSC derived endothelial-based tumor vaccine which has demonstrated efficacy in animal models of breast cancer.
Konghusker wrote: Wed Nov 24, 2021 7:47 am Where exactly are you on the stemvacs timeframe? What’s the next step and how far out is this roughly for being a realistic treatment for cancer treatments in the US? I know jadicells is the current excitement, but I originally got in for this cancer treatment and am just curious about the process/steps and where it is in the process. It’s what I’m most excited about due to cancer affecting so many people I know. Thanks Tim, and happy thanksgiving.
Konghusker
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Re: StemVacs-P iPSC

Post by Konghusker »

Thanks for the info Tim. The results from the 10 patients is what got me excited for hopefully a more effective treatment coming. Hopefully stemvacs is a very effective approved treatment someday, and hopefully sooner than later. We need hope. Thanks again
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TimGDixon
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Re: StemVacs-P iPSC

Post by TimGDixon »

Too many friends and loved ones for all of us are gone because of it. The big step forward here is that we can give a consistent # of cells. In the prior trial those vaccines were made from the patients own blood. Due to their degree of illness we yielded inconsistent numbers. This 3rd generation now provides a universal cell that allows us to administer a specific number of cells per dose. In the upcoming its a total of 40 million cells but administered weekly at 2.5 million cells per treatment x 16.
Konghusker wrote: Wed Nov 24, 2021 11:48 am Thanks for the info Tim. The results from the 10 patients is what got me excited for hopefully a more effective treatment coming. Hopefully stemvacs is a very effective approved treatment someday, and hopefully sooner than later. We need hope. Thanks again
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