Biological Disruptive Therapies as Counter Measures for Unpredictable Biological Insults, a Case for Successful Treatment of COVID-19

Treatment of patients with severe COVID-19, is challenging specifically when a patient carries high risk of mortality, such as old age, immune suppression or cancer. Also a patient who manifests the disease with severe symptoms, such as hypoxia, requiring supplemental oxygenation, or artificial ventilation has a poor prognosis. Here we review the scientific rationale used to design a very promising therapy based on existing literature, but in significantly dif-ferent method and protocols, used to treat cases of severe COVID-19, and we conclude that although the effort on drug development has been enormous, but as of today, we do not have a therapy with specific characteristics as this protocol, to be used safely in human and yet potentially meet the expectations we would have for a so called “effective therapy”. Further clinical trials are needed to support this hypothesis and generate further hypothesis to prove the concept in larger cohort of patients.


Background
Severe COVID-19 is a deadly disease in patients with cancer, or the patients who are on steroids or other immune suppressing conditions. The data have shown inferior results in outcome in these groups. Men also have higher risk of significant comorbidity and death. Among them, aged 75 and more are specifically at DOI: 10 These findings indicate that cancer patients appear more vulnerable to SARS-COV-2 outbreak. Since this was the first large cohort study on this topic, the report will provide the much-needed information that will benefit global cancer patients. As such, the study was suggested to be disseminated widely to alert clinicians and patients [1]. Further initial results of the registry study of the  [13].
The question of quantity of human response to any of the proposed therapies, however seemed always to be a challenging question as the magnitude of response was always suboptimal in cases with severe disease, such as pneumonia or acute respiratory distress syndrome (ARDS), a severe inflammatory response in Cov19, manifested by lactate production secondary to activation of hypoxic cascade [14]- [20].
Recently there has been a significant effort in screening Chinese herbs and compounds to find a treatment which could disrupt the virus replication by inhibition of specific enzymes, dictated by specific genes [21]. These efforts yielded scientists in the field to believe that there is a potential therapy that could be used with no sign of resistance, at a dose dependent level, and yet has potentials for inhibition of selective Phosphoinositol kinase (Pi3K). This is a unique enzyme involved in growth of many solid tumor types, including breast cancer.
There was enough clinical experience in our clinic, to use this compound in the form of intravenous application, to understand the exact clinical response in cancer patients, but no patient with COVID-19 was treated.

Methods and Results
Quercetin was identified as the most potent inhibitor of the screened molecules to inhibit Pi3K mutated gene, based on laboratory findings [21] [22] [23] and was administered per (multi targeted epigenetic therapy) MTET protocol.
To date, 52 patients with activating mutations identified in their liquid biopsy test by Guardant 360, were treated with this protocol, with serial monitoring of the response, through 250 test samples. These cases were tracked and their mutated allele frequencies measured longitudinally to document response and correlate with the clinical outcome. There was 89 percent response post treatment. Patients aged from 24 to 80 and the male/female ratio was 0.7. Duration of therapy was between 2 weeks to 5 years, with minimum of ten treatments between the test/re test.
Here we present samples as cases to this article: Case 1: 70 years old male with history of prostate cancer Gleason score of 9, diagnosed in April 2017, status post radiation as well as hormonal blockade with Lupron and Zytiga, so far he has received 2 shots of Lupron, at 3 months interval, PSA has decreased from 19 to 5. Patient has some urinary hesitation after the radiation, as well as severe fatigue.
Upon his arrival he was evaluated for metastatic disease with a whole body PET scan, which showed extensive bony mets, all through his pelvis, and vertebras. His liquid biopsy on 10/24/17, showed positive c DNA for TP53, BRCA, PDGF, and APC. He was immediately started on IV epigenetic therapies which he received on daily basis, for two weeks, his labs were further repeated. His Prostate acid phosphatase dropped from 71 to 66. His PSA dropped from 11 to 7. During this time, he had stopped his Zytiga, and did not receive any conventional therapies. His quality of life improved and he no longer had fatigue. His bone scan was repeated on 12/2/17, which showed stable disease. His labs show on 1/23/18, that his TGF had dropped from 5207 down to 3372, and his PAP dropped from 71.6 to 70.8 (stable).
He further was started on Gleevec along with epigenetic therapies, and continued to respond clinically to the therapy. Noticeably he did not receive any hormonal blockade.
His PSA was checked on 2/14/18 and it was down to 3.3 from 7.2 (measured on 2/14/18 and 12/7/17 respectively. He was restaged with a whole body PET scan on 3/13/18 which showed sclerosis and healing of all his bony lesions as well as resolution of his paraaortic LN. His CTC was repeated on 5/22/20 and it showed drastic reduction of ERBB2 and telomerases. (see below). His PSA also dropped from.9 in may 2020, to 6.8 on 6/22/20, after the course of treatments.
On 5/17/2020 he randomly was tested for COVID-19, due to his exposure in NY. He was tested positive for COVID-19 antibody test (Both IgG and IgM)but negative for the antigen test (PCR) performed on 5/20/2020, and yet did not have any symptoms, as he was treated for his prostate cancer with same treat-  (Figure 1). Case 2: The case report related to this article has the most criteria for the worst outcome, expected from this disease. The case is a 77 year old male with history of mantle cell lymphoma treated for over 10 years by our clinic. He was initially diagnosed on 10/25/2011 with an orbital mass, confirmed by pathology status post Maxi-ChopX 4 cycles, protocol referred to us for metabolic and epigenetic evaluation and treatments. He refused further chemotherapy secondary to severe side effects. His labs were drawn on 1/30/2012 which revealed increased LDH. His pathology originally was positive for both bcl and Ki 67 and his macroglobulin was elevated, all suggestive of poor prognosis and aggressiveness of his cancer.
His initial labs showed LDH of 252, and ferritin of 850 and presence of metamyelocytes and myelocytes. Immediately he was started on the epigenetic and antioxidant IV protocol. After three sessions his fatigue improved and his function Advances in Infectious Diseases increased. After 5 treatments, his labs were repeated. His LDH (tumor marker) dropped to 231, his ferritin to 509 and his beta 2microglobulin showed normal results, when increased levels were seen in his electrophoresis before starting the treatments.

Conclusion
This case report although small is sample size has significant relevance and statistical effect size. We certainly understand the limitations of the study including the lack of randomization or placebo control, but we also recognize the lack of effective therapies in this scenario, making it difficult to ethically treat a patient  with COVID ARDS with placebo. We observed unexpected results with positive clinical outcome in most difficult to treat patient with high risk of mortality. We recommend further studies to prove the concept on application of this protocol on larger groups of patients as critically ill to supplement the conclusion.

Conflicts of Interest
The author declares no conflicts of interest regarding the publication of this paper.