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abstracts
Annals of Oncology
32
A new therapeutic approach to auto-immune diseases: Endotherapia
L. Vidal, A. Mangas, M. Geffard
GEMAC S.A., France
Background: Endotherapia is a new therapeutic approach to chronic pathologies,
including auto-immune, neurodegenerative and proliferative diseases such as Multiple
Sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS), Rheumatoid Arthritis (RA),
Stroke, etc. Endotherapia is based on a patho-physiological concept that takes into account genetic predisposition and immunological, bacterial environmental factors. It
includes: a) clinical aspects: para-clinical and biological exams (MRI, etc. . .), allowing
an exact diagnosis; b) identification of specific circulating antibodies in the serum of
patients; c) the use therapeutic tools with small compounds linked to Poly-L-lysine,
each compound with their physiological actions being known. After biological and
medical data collected, the therapy proposed is a “tailor-made” combination of PLL
compounds, as active ingredients.
Methods: Endotherapia is based on a concept that takes into account the genetic predisposition and medical events, together with bacterial and environmental factors. The
biological follow up using circulating antibody assays in the serum of patients suffering
from chronic diseases, these circulating antibodies are directed against NO and IDO
modified or non-self-antigens, response against bacterial antigens; the use of innovative
therapeutic tools. The synthesised active ingredients used in Endotherapia are based on
linked small molecules (i.e., vitamins, fatty acids, anti-oxidants, scavengers) to a nonimmunogenic chain of PLL. Many “tailor-made” combinations named GEMSP for
MS, GEMALS for ALS, composed of 20-25 PLL compounds.
Results: Endotherapia is a promising therapy for chronic diseases, with no side effects,
which is evidently mandatory in the management of long-term pathologies, having a
neuroprotective effects, allowing to delay the evolution of disease, to control oxidative
stress and inflammation. Each PLL compound offers great advantages, such as an increase in the half-life of the active small molecules. Endotherapia involves clinical aspects, allowing an exact diagnosis of the disease and the identification of specific
circulating antibodies in the serum of patients in several clinical trials.
Conclusions: Endotherapia intervenes in several pathogenic mechanisms and shows a
good safety profile. Endotherapia has been shown to be efficacious in an open clinical
trial for RA in Strasbourg. 21 patients received 2 subcutaneous injections of the “tailormade” combination MG1/RA/day over 90 days. In the statistical analyses performed,
18 out of 21 patients were analysable. An improvement was observed in 61% of the patients, which was very promising, with a very low incidence of adverse effects linked to
the treatment was found. One of the most advanced applications of Endotherapia is the
treatment of MS with GEMSP. In an open clinical MS trial (phase IIa) in 2003-2005, 22
secondary progressive-phase patients were treated with a sublingual formulation over
six months; 55% of the patients became stabilised or their EDSS was decreased (18%),
instead of the normal progression of the disease, and only 27% of the patients followed
a normal disease progression.
Legal entity responsible for the study: GEMAC S.A.
Funding: Private and public investments
Disclosure: All authors have declared no conflicts of interest.
Volume 28 | Supplement 7 | October 2017
33
A model based adjustment for tumor mutational burden across different
tumor types
M.H. Wang1, W.W. Shi2, P. Zhang2,3, S.H. Zhao2, J.Y. Cao4, M.W. Chen5, T. Shou6, J. Hu7,
X.F. Tang7, T.Q. Song8
1
Sun Yat-Sen Memorial University, Guangzhou, China, 2OrigiMed, Inc., Shanghai,
China, 3Center of Precision Medicine, Zhejiang University International Hospital,
Hangzhou, China, 4The Affiliated Hospital of Qingdao University, Qingdao, China, 5The
First Affiliated Hospital of Guangxi Medical University, Guangxi, China, 6First People’s
Hospital of Yunnan Province, Kunming, China, 7The First Affiliated Hospital, Zhejiang
University School
Background: Tumor mutational burden (TMB) has proven to be significantly related
to clinical benefit from immunotherapies. However, its variance across different tumor
types is not well characterized, especially when it is estimated from panel sequencing
assay, which is typically biased by the selection of the genes targeted by a specific panel.
Methods: Whole exome sequencing (WES) data from seven tumor types (lung, breast,
melanoma, esophagus, colorectal adenocarcinoma, liver, and stomach cancers) including 2,066 cancer specimens from TCGA was examined for TMB. TMB was assessed
from the whole exome for WES TMB (or WTMB) or from 450 genes targeted by a specific sequencing panel (YuanSuTM) for un-adjusted panel TMB or UPTMB. The latter
was modeled to adjust for variance among the 7 tumor types as adjusted panel TMB or
APTMB.
Results: Although both UPTMB and APTMB were significantly associated with
WTMB (R2 ¼ 0.97 and 0.99, respectively), they were modestly predictive of WTMB
when it was lower than the median (R2 ¼ 0.43 and 0.46, respectively). Furthermore, we
observed the significant difference in the number of somatic mutations between targeted and un-targeted regions of YuanSuTM panel across different tumor types (e.g. pvalue ¼ 1.6 x 10161 between liver and melanoma cancers, Fisher test). This indicated a
potential bias in using UPTMB to assess WTMB in general panel sequencing.
Alignment of WTMB, UPTMB and APTMB across all types showed APTMB was more
consistent with WTMB than UPTMB. As expected, significant difference was found between WTMB and UPTMB (p ¼ 0.019, paired t-test) but not between WTMB and
APTMB (p ¼ 0.14, paired t-test), which confirmed the adjustment is necessary.
Clinically, both UPTMB and APTMB were significantly associated with progress free
survival (PFS) of anti-PD-1 therapy (pembrolizumub) in non-small cell lung cancer
(Rizvi, et al.) with the same log-rank P as 0.018. In its initial application, our algorithm
successfully identified two patients with high APTMB and recommended for pembrolizumub treatment: the one with advanced squamous cell lung carcinoma responded to
pembrolizumub for 19 months; while the other, an advanced intrahepatic cholangiocarcinoma achieved a complete response from the combination of pembrolizumub and
chemotherapies.
Conclusions: Adjusted panel TMB is more reflective of TMB from WES than unadjusted one, and the adjustment is necessary when different tumor types are concerned. This speculation could be applicable to other panel platforms. Importantly,
APTMB successfully exhibits its clinical utility in selecting patients for proper immunetherapy.
Legal entity responsible for the study: Origimed, Inc., Shanghai, China
Funding: Origimed, Inc., Shanghai, China
Disclosure: P. Zhang, S.H. Zhao, Kai Wang and W.Wi Shi are employees of Origimed,
Inc., all other authors claim no conflicting interests.
doi:10.1093/annonc/mdx509 | vii13
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