On this page of StockholderLetter.com we present the latest annual shareholder letter from CEL SCI CORP — ticker symbol CVM. Reading current and past CVM letters to shareholders can bring important insights into the investment thesis.

 •  3/7/2024 Letter Continued (Full PDF)
 •  5/8/2015 CVM Stockholder Letter
 •  6/8/2016 CVM Stockholder Letter
 •  4/27/2017 CVM Stockholder Letter
 •  8/8/2018 CVM Stockholder Letter
 •  3/26/2019 CVM Stockholder Letter
 •  3/4/2020 CVM Stockholder Letter
 •  4/29/2022 CVM Stockholder Letter
 •  4/10/2023 CVM Stockholder Letter
 •  More "Biotechnology" Category Stockholder Letters
 •  CVM Benford's Law Stock Score = 69

CVM Shareholder/Stockholder Letter Transcript:

Annual Report
2023

CEL-SCI   s Corporation
CEL-SCI Corporation is a clinical-stage biotechnology company dedicated to research and development directed at
improving the treatment of cancer and other diseases by using the immune system, the body   s natural defense system.
CEL-SCI is currently focused on the development of the following product candidates and technologies:
1) Multikine, an investigational immunotherapy under development for the potential treatment of certain head
and neck cancers; and
2) L.E.A.P.S. (Ligand Epitope Antigen Presentation System) technology, or LEAPS, with several product
candidates under development for the potential treatment of rheumatoid arthritis.
None of CEL-SCI   s product candidates have been approved for sale, barter or exchange by the Food and Drug
Administration (FDA) or any other regulatory agency for any use to treat disease in humans nor has the safety or
efficacy of these products been established for any use. There can be no assurance that obtaining marketing approval
from the FDA in the United States and by comparable agencies in most foreign countries will be granted.
MULTIKINE AND THE PHASE III CLINICAL TRIAL RESULTS
Immunotherapy is a large, high growth market. Immunotherapies use the patient   s own immune system to fight
disease. These    targeted therapies    are at the forefront of modern cancer research. A recent Bloomberg report from
January 2023 asserted that:
The global cancer immunotherapy market is expected to reach USD $196.45 billion by 2030,
registering CAGR of 7.2% during the forecast period, according to a new report by Grand View
Research, Inc. The rising adoption of immunotherapy over other therapy options for cancer owing
to its targeted action is anticipated to increase the adoption during the forecast period. Moreover,
increasing regulatory approvals from authoritarian establishments for novel immunotherapy used
for oncology is also expected to further fuel the market growth.
Source:
https://www.bloomberg.com/press-releases/2023-01-18/cancer-immunotherapy-market-worth-196-45billion-by-2030-grand-view-research-inc
CEL-SCI hopes to participate in this growing market with its lead investigational therapy Multikine   (Leukocyte
Interleukin, Injection). Multikine has already been tested in approximately 750 human patients in multiple clinical
trials, including a well-controlled, multicenter, global, 928 patient Phase III randomized controlled trial. Multikine is
unique among approved cancer immunotherapies because it is given first, right after diagnosis and before surgery.
CEL-SCI believes that the Phase III clinical trial demonstrated that Multikine caused tumors to reduce in size and/or
caused the disease to    downstage    within just a few weeks of treatment before surgery. Importantly, patients with
these reductions and/or downstages had their risk of death cut in half at five years of follow up. CEL-SCI is discussing
with regulators in Europe, the U.K., the U.S., and Canada with a view to obtaining marketing authorization and
approval for immediate patient access to Multikine without waiting for the results of a confirmatory trial.
In 2023, the Multikine target patient population is estimated to include about 145,000 patients per year worldwide,
with more than two-thirds of those outside the United States. Global growth rates of eligible cases are expected to rise
30% by 2030. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10304137)
What is Multikine and who is it for? Multikine is a biological medicinal immunotherapy comprised of a mixture of
natural cytokines and small biological molecules. Multikine is injected around the tumor and adjacent lymph nodes
for three weeks as a first-line treatment before the standard of care (SOC), which is surgery followed by either
radiotherapy or chemoradiotherapy. Multikine   s rationale for use is to incite a locoregional immune response against
the tumor before the local immune system has been compromised by the standard of care and/or disease progression.
The Multikine target population is treatment-na  ve adult patients with resectable locally advanced primary squamous
cell carcinoma of the head and neck (SCCHN) in the oral cavity or soft palate and who have:
No lymph node involvement (via PET scan)
Low PD-L1 tumor expression (TPS<10) (via biopsy)
PD-L1 is a protein receptor on the tumor cell surface that helps the tumor repel the immune system. CEL-SCI believes
that patients with tumors having low PD-L1 would be more likely to respond to Multikine because their tumors have
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lower defenses against the patient   s immune system. CEL-SCI estimates that patients with tumors having low PD-L1
represent about 70% of locally advanced primary SCCHN patients.
Multikine leads to longer survival with no safety issues. Clinical investigations of Multikine have demonstrated in
the randomized controlled Phase III trial (RCT) the following in the target population:
risk of death cut in half at five years versus the control;
28.6% absolute 5-year overall survival benefit versus control (p=0.0015);
0.349 hazard ratio vs control (95% CIs [0.18, 0.66], Wald p=0.0012);
>35% rate of pre-surgery reductions and/or downstages (p<0.01); and
low PD-L1 tumor expression (vs high PD-L1 where Keytruda and Opdivo work best).
There were no demonstrable safety signals or toxicities observed in approximately 750 Multikine-treated subjects
across multiple clinical trials. Adverse event (AE) and serious adverse event (SAE) incidences were not significantly
different among treatment and control groups. There were no Multikine-related deaths and only two discontinuations.
Multikine-related AEs before surgery were local and resolved after surgery. Although the literature reports that some
of Multikine   s components may be toxic when adm
did not emerge with Multikine, even at doses many times higher than those administered in the Phase III trial, primarily
due to Multikine   s delivery by local injection and dosage.
CEL-SCI published its data as abstracts and posters at the annual conferences for the 2022 American Society of
Clinical Oncology (ASCO), 2022 and 2023 European Society for Medical Oncology (ESMO), the 2023 European
Head and Neck Society   s (EHNS   s) annual European Conference On Head And Neck Oncology (ECHNO), the 2023
European Society for Therapeutic Radiology and Oncology (ESTRO) and the 2023 American Head and Neck Society
(AHNS). These publications can be accessed at http://www.cel-sci.com.
Multikine works by inducing pre-surgical responses. CEL-SCI observed statistically significant pre-surgical
responses after Multikine treatment, and therefore CEL-SCI believes in the following:
Multikine causes pre-surgical responses;
Pre-surgical responses lead to longer life;
Therefore, selecting more patients predicted to have a pre-surgical response should lead to much better
survival in the target population.
A    pre-surgical response    is a significant change in disease before surgery. CEL-SCI saw two kinds of responses in
the Phase III trial. First, there were    reductions    in the size of the tumor   a reduction of 30% or more qualified as a
   pre-surgical reduction    or    PSR    for short. Second, there were disease    downstages,    (e.g., the disease improved
from Stage IV to Stage III) pre-surgery. CEL-SCI calls this a    pre-surgical downstaging    or    PSD    for short. CELSCI   s 2022 ESMO cancer conference presentation reported on PSR, and CEL-SCI   s new 2023 ESMO presentation
reported on PSD.
Across the whole Phase III trial, PSRs were seen in 8.5% of Multikine patients compared to none in the control group.
PSDs were seen in 22% of Multikine patients as compared to 13% in the control group. Because Multikine was the
only therapy given to these patients before surgery, it is CEL-SCI   s strong belief that Multikine had to be the cause of
the higher rates of PSR and PSD.
These data are presented visually below. The taller blue columns show PSR and PSD rates in all 529 Multikine-treated
patients in the Phase III trial, and the gray columns show PSR and PSD rates for all 394 control patients. The p-values
above the columns show comparisons between Multikine and the control groups. With Multikine, statistically
speaking, CEL-SCI believes there is a better than a 95% chance that the increases in PSR/PSD in the Phase III study
were caused by Multikine.
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It was not enough for us to show that Multikine likely leads to PSRs and PSDs as compared to a control group, CELSCI also had to test if PSRs and PSDs lead to improved survival. CEL-SCI   s Phase III trial demonstrated that PSR
patients were 72% likely to be alive after five years, whereas control patients were only about 49% likely to be alive
after five years. Patients with PSD saw similar improvement in CEL-SCI   s Phase III trial. Their five-year chance of
survival was approximately 68%. Therefore, CEL-SCI   s Phase III trial demonstrated statistically that those patients
who had PSR or PSD resulting from Multikine lived longer than those who were not treated with Multikine. It is
important to note that these results are from the entire Phase III study population, not from a subgroup. The p-values
of less than 0.005 means there was at least a 99.5% chance that these results are due to Multikine rather than random
chance. The likelihood of living at least five years is shown in the graphic below for patients with PSR (blue), patients
with PSD (orange) and patients who did not receive Multikine (gray).
CEL-SCI   s target population can be readily selected by doctors upon diagnoses using standard tests. Having
shown a potential causal link supported by strong statistics between Multikine and survival benefit, CEL-SCI believes
that Multikine should be approved quickly. But recall that the Phase III study   s primary endpoint of 10% survival
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benefit was not met. How then can we say that Multikine actually benefits patients? The answer is that while Multikine
has shown that it can help patients with PSR/PSD, there were not enough PSR/PSD in the Phase III study population
to yield a 10% survival benefit for the whole population. In other words, the benefits from PSR/PSD were too diluted
when averaged with the other patients in the study.
None of this changes the fact that CEL-SCI observed statistical significance when analyzing Multikine   s ability to
cause PSR/PSD and that these PSR/PSD statistically appear to lead to a higher chance of living five years or longer   
CEL-SCI simply had to define a target population who would have a larger number of PSR/PSD. To do so, CEL-SCI
analyzed Multikine   s biological mechanism of action, talked to regulators and physicians who knew best, and were
guided by the Phase III data, including patient-specific data down to the cellular level. All this of course took time,
but CEL-SCI believes it has succeeded and is ready to move forward.
One of the first things we reported from the Phase III study was that Multikine was shown to work best in patients
who were deemed    low risk    after surgery, about 40% of the study population. These patients saw a significant 14.1%
absolute 5-year survival benefit vs the    low risk    control group not receiving Multikine. It made sense biologically
that these patients would benefit most from Multikine, because they tended to have immune systems that were not yet
compromised by the disease.    High risk    patients, by contrast, typically had lymph nodes invaded by the tumor, and
needed chemotherapy after surgery. Because their lymph nodes were compromised, this made it harder for their
immune systems to work, and they needed surgery as soon as possible without waiting an extra three weeks to receive
Multikine. CEL-SCI initially developed criteria for selecting    low-risk    patients at diagnosis   i.e., those having no
lymph nodes invaded by the tumor (N0) or only one lymph node invaded by the tumor (N1) as well as no extracapsular
spread as determined by PET scan. CEL-SCI published these criteria at the ASCO conference in 2022. However, after
discussions with regulators and physicians, CEL-SCI saw that outcomes could be improved further if the N1 patients
were excluded, and only the N0 patients were included in the target population.
CEL-SCI also saw from the Phase III data that Multikine was more effective for patients with low PD-L1 tumor
expression than for patients with high PD-L1 expression. This analysis was pre-specified in the statistical analysis
plan. Targeting low PD-L1 also differentiates Multikine from other immunotherapies. For example, checkpoint
inhibitors like Keytruda and Opdivo appear to best serve patients having high PD-L1, because these drugs work by
blocking PD1/PD-L1 receptors interaction; when this interaction (PD1/PD-L1) happens it leads to inactivation/death
of the immune cells attacking the tumor. While none of these drugs are currently approved as a first-line treatment
before surgery, even if such approvals were to come in the future, the large majority of patients in this group having
low PD-L1 would still be expected to need Multikine.
CEL-SCI   s target population is now directed to patients who present at diagnosis with N0 nodal involvement and also
with low PD-L1 tumor expression (defined as tumor proportions score (TPS) < 10). These patients can be readily
identified upon diagnosis with tests that physicians routinely use in cancer screening, a crucial achievement towards
Multikine becoming available for use. For instance, a PET scan should be used to determine the N0 nodal status and
a screening tumor biopsy should be used to determine the low PD-L1 expression. Doctors already routinely screen
head and neck cancer patients using PET scans and biopsy. Therefore, doctors can screen for Multikine patients
without new tests or new costs.
Multikine cut the 5-year risk of death in half in the target population. CEL-SCI   s results show that Multikine can
cut the risk of death in half at five years versus the control group in the finalized target population. Survival increased
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 3/7/2024 Letter Continued (Full PDF)