Abstract
This unique “PERSPECTIVE” on Targeted Genetic Medicine for Cancer represents the third manuscript in a series of medical oncology papers by gene therapy pioneers, Gordon and Hall, a combined medical oncologist’s and layman’s trilogy recorded with the following intents and purposes: (i) documenting significant milestones in clinical oncology for the medical community, (ii) honoring forthright principles of “Informed Consent” for the advanced/refractory oncology patient, and (iii) confronting logical fallacies of popular opinion, in light of recent critical analyses of long-term cancer-free survival data. As with the two previous historical “perspectives,” the authors present noteworthy up-to-date clinical research documenting the successful management of refractory metastatic cancers with tumor-targeted gene therapy vectors—validating “Pathotropic” (disease-seeking) tumor targeting Avant la Lettre. This paper provides additional insights into the molecular and cellular mechanisms of both tumor-targeting and tumor-eradication. As with the prior two papers, the authors utilize the revealing powers of allegory and classic literature, adding shared iconic cinematic experiences of postmodernism at times, to educate, inform, and convey the formidable yet verifiable and important hard-core science (that is, the fundamental chemistries, biophysics, molecular biology, genetics, stem cell biology, regulatory biology, synthetic virology, tumor immunology, clinical oncology, bio-pharmacology, histopathology, and cancer gene therapy) embodied within the “smart” therapeutic nanoparticle, DeltaRex-G: a refined “primal-hunter” & “tumor-killer” that actively seeks out the cryptic/hidden “Biochemical (Jailbreak) Signatures” of metastatic cancers, delivers targeted gene therapy “precisely”totumor cells, and ultimately eradicates both primary and metastatic lesions, including lymphatic metastases. Accomplishment of the “DeltaRex-G Rescue-Mission of 2019” with updated FDA regulatory approvals and sustainable/scalable cGMP bioproduction is considered opportune—while the Right-to-Try experimental therapies legislation in the United States comes face-to-face with the U.S. FDA approval of Expanded Access for DeltaRex-G for advanced pancreatic cancer and sarcoma, and compassionate use for all solid tumors—as such, the authors embrace the legitimate rights of the cancer patient to be more fully informed of such beneficial treatments currently available in the United States.
Highlights
Forty—forty—forty years ago! —ago! Forty years of continual [hunting]! forty years of privation, and peril, and storm-time! forty years on the pitiless sea! for forty years has Ahab forsaken the peaceful land, for forty years to make war on the horrors of the deep! (Moby Dick, Ch.132, by Herman Melville, 1851).Forty—forty—forty—years, added together!! Forty years of continually hunting monsters!! forty years of privation, and peril, and storm-time!! forty years on the pitiless sea!! for forty years have Gordon and Hall forsaken the peaceful land to make war on the horrors of The Deep!! [1, 2]
The “true” yet largely unaware and hugely ironic nature of reality—in this case —is the horrifying and yet undeniable tragic fact: that the Victorian sailors upon which Herman Melville crafted the Epic-Moby-Dick-Meta-Story had all admittedly expressed a collective, paralyzing fear of so-called “cannibals:” the savage South Pacific Islanders of the local Marquesas Islands, which misguided the shipwrecked sailors— the remaining lifeboats—out into open waters where storm-time, peril, and privation of basic human needs reached monstrous proportions—only to realize that the “cannibals” they feared most are present within each and every one of us—amid “our own” natural mob/ herd of some thirty trillion cells that make up a given multicellular Person of Substance: You, dear reader; me and she and thee
Renewed interest in the Tumor Microenvironment (TME) notwithstanding, numerous attempts at combining ungoverned chemotherapy with unguided immunotherapy have been hampered, often stymied, by off-target side-effects which consistently lead to rather serious clinical adverse events: “A significant fraction of patients treated with chemo-immunotherapy exhibited immune-related adverse events of grade 3 or higher, with a 10-20% rate of treatment discontinuation owing to severe adverse events associated with chemoimmunotherapy” [72–75]
Summary
Forty—forty—forty years ago! —ago! Forty years of continual [hunting]! forty years of privation, and peril, and storm-time! forty years on the pitiless sea! for forty years has Ahab forsaken the peaceful land, for forty years to make war on the horrors of the deep! (Moby Dick, Ch.132, by Herman Melville, 1851). The FDA-deputized Nano-Dino-Hunter from our evolutionary past is an adaptively-engineered, artfully-designed, minimalistic, biocompatible, vWFD2derived, experimentally optimized and selected “HUNTER” aka gene therapy vector deployed clinically: (i) to map-out out the biochemical Tierra Incognita of OUR histological Inner Dark; (ii) to deliver precision Cancer Gene Therapy (with increased safety, efficacy, outcomes) to human metastatic cancers [59] At the time, it was a road less traveled:. In this case, the blue-colored buffalo demon represents the allegorical/histological Outlaw DNAÀDamaged cancer cell, amid a myo-fibroblastic cloud (desmoplastic stroma) of cytological hostages, immunesystem on-lookers, and vascularizing accomplices (tumor angiogenesis), which threaten the stability of the ‘cosmos.’ The invincible, ever-resourceful Mounted Durga shows a Decisive Multi-Pronged Approach: (i) to restore anergic (timid) immune responses, (ii) to destroy supportive tumor-associated vasculature, and (iii) to directly eliminate the rogue cancer cells (i.e., the blue buffalo demon) which are selfishly, flagrantly driving cancer metastasis.
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