Timeline

Personalized Tumor Neoantigen-Specific Vaccine Treatment

Dr. Saskia Biskup

Saskia Biskup, MD, PhD, is a group leader at the Hertie Institute for Clinical Brain Research in Tuebingen, Germany.  She is the Managing Director of Cegat, and her company is developing a unique vaccine targeting cancer patients.

The doctor says, “Changes in the genetic material (genome) of a single cell are responsible for the development of cancer. Most errors in the genome are immediately repaired by the cells without causing permanent damage.”

The oncologist is often faced with the problem of which of the many available drugs to use. More and more drugs are available that work precisely when specific genetic changes are present in the tumor. Until recently, tumors were examined for only a few, if any, genetic changes that were common in the respective tumor entity. It is now clear, however, that every tumor is individual and, due to specific genetic changes, can be susceptible to drugs that have not been considered before. A comprehensive genetic examination of the tumor can thus help

So, I will be taking tumor samples and sending them to them until we get the tumor exome analysis within 4 to 6 weeks.

Before my second surgery, I had several calls with her.  After giving her a sample post-surgery, I learned from her that if the outcomes showed paths for success, it would take them 2 months to prepare the vaccine, and I’ll be asked to fly once every 4 to 6 weeks for probably two years. The variables cannot be determined until the assessment is over.  

She informed me of the following:

The ultimate aim is to train and activate the immune system to recognize and destroy tumor cells. Mutation-derived novel protein sequences (neoantigens) are presented on the surface of tumor cells via HLA molecules. The immune system has the ability to recognize these neoantigens as foreign structures and, as a consequence, specific immune cells (cytotoxic T cells) are activated to kill tumor cells.

Every single patient shows individual tumor-specific (somatic) mutations. Some of these mutations lead to novel protein sequences which are potentially immunogenic (neoantigens). To identify such tumor-specific mutations, exome analyses of DNA from tumor and blood (normal control) are performed using next-generation sequencing. At this stage you have already received a report of somatic tumor variants from us summarizing the therapeutically relevant mutations identified in your tumor.

Additionally, bioinformatic prediction algorithms are subsequently being used to identify those mutated peptides which are most probably presented on the cell surface of your tumor and have the potential to elicit an immune response. Standardized selection criteria are applied to select the most promising neoantigen-harboring peptides. You have already received the report with the selection of 19 peptides (neoantigens). All of those peptides will be included in your personalized peptide vaccine, depending on solubility. As solubility of peptides cannot be reliably predicted before synthesis, it cannot be guaranteed that all ordered peptides can be dissolved and included in the final vaccine. Peptides which have been proven problematic will be reported upon at vaccine release. Upon your agreement, the peptides will be chemically synthesized and formulated into an injectable vaccine. The whole process will take about 10 to 12 weeks, including quality control and release of the vaccine.

Peptide vaccines by themselves are in general weakly immunogenic. Hence, your personalized peptide vaccine is applied in combination with an adjuvant – typically a recombinant GM-CSF such as the FDA approved Leukine® – to increase stimulation of your immune system and will be injected subcutaneously. Repeated intradermal vaccinations will be performed in my practice regularly according to a fixed treatment plan. The plan includes a priming phase (4 vaccinations within 10 to 12 days) followed by another 23 vaccination sessions.

To the best of our knowledge and according to our experience, the treatment is well-tolerated. However, our personalized peptide vaccine must still be considered as an experimental therapeutic approach and hence its efficacy cannot be guaranteed.

Results Prior to Starting

Feb 2021
They shared the following two reports with me already, as below:

Neoepitope Prediction and Peptide Selection 

Results
19 peptides were selected based on the neoepitope prediction results of your patient’s tumor sequencing data. 
The selected peptides are predicted to activate not only cytotoxic T cells but also T helper cells. Therefore, in addition to short peptides (8-12 amino acids) potentially binding to HLA class I molecules, long peptides (-17 amino acids) potentially binding to HLA class II molecules were also included. 
(3 pages, download here)
 
Report of Somatic Tumor Variants
Results
  • We detected variants with potential therapeutic relevance in the current sample.  
  • No evidence of therapeutically relevant variants in genes CDKN2A, CDKN2B, EGFR (amplifications, activating mutations). 
  • No detection of a pathogenic/likely pathogenic germline variant. 
 (9 page, download here)

And then I was very well informed on the process, the number of visits, and more.  Everything they shared with me was very professional, for sure.  After reading the details of the results, I decided to move on.

First Trip

(4 vaccinations in one visit)

The Report

The below is the outcome that I have received after the first visit to the doctor’s office (and Germany).
We have met four times to induce the immune response. As you know, the aim of the treatment with the personalized vaccine in Germany is to activate the patient’s own immune system to recognize and destroy tumor cells. The mechanism takes advantage of the fact that the tumor cells are distinct from normal cells and can be recognized by specialized immune cells if those are trained against the tumor cells. Tumor mutations are highly patient- and tumor-specific, and some of those lead to the production of novel protein sequences. The tumor cells present some of those mutation-derived novel protein sequences (neoantigens) on their surface. These neoantigens are different from those in normal cells, and tumor-specific T cells can recognize them.
 
To use this knowledge for vaccine development, we first identified the tumor-specific mutations. To identify such mutations, we performed exome analyses of DNA from both tumors (malignant tissue) and from the blood (as normal control) using next-generation sequencing
 
The analyses included:
  • Whole-exome sequencing of tumor and normal tissue
  • Whole tumor transcriptome
  • Identification of tumor-specific nonsynonymous mutations (mutations that may lead to altered protein sequences)
  • Compilation of a clinical report including treatment recommendations
  • Genotyping of the patient’s HLA molecules
  • Prediction of which tumor-specific mutated peptides are most probably presented on the tumor cell surface by the patient-specific HLA types using novel computational methods
  • Database analysis to investigate the expression of the respective genes in this tumor type
  • Analysis of which peptides can be synthesized and dissolved in an injectable solution
  • Selection and recommendation of peptides that are predicted to elicit the most powerful immune response against the tumor: compilation of reports

Based on these analyses, to manufacture the personalized tumor neoantigen-specific peptide vaccine, the following steps have been performed:

  • Synthesis of the desired number of peptides
  • Preparation and quality control of the injectable multi-peptide vaccines (sufficient doses for one year)

The personalized vaccine is applied along with an adjuvant (typically GM-CSF, Leukine®, or Aldara®) to increase the stimulation of the immune system.

Repeated vaccinations are now being performed regularly according to a fixed treatment plan. The plan includes:

  • A priming phase (4 vaccinations within 10 to 12 days) and
  • Subsequent monthly injections for about 10 months
First vaccination: August 23, 2021

Application of the personalized vaccine together with Aldara® and Leukine® and blood draw for immune monitoring

Second vaccination: August 24, 2021

Application of the personalized vaccine together with Aldara® and Leukine®

Third vaccination: August 25, 2021

Application of the personalized vaccine together with Aldara® and Leukine®

Fourth vaccination: August 26, 2021

Application of the personalized vaccine together with Aldara® and Leukine®

After these priming injections, we recommend administering booster vaccinations every 4 to 6 weeks.  To the best of our knowledge and according to our experience, the treatment is generally well tolerated.  We were happy to see that you tolerated the first four vaccinations very well.

Monitoring the immune response to the treatment is important for gauging its success and can help prevent potentially more severe side effects. As such, immune monitoring is strongly recommended as an important
monitoring mechanism along with the vaccine treatment. We recommend doing the monitoring when Mohammed Banat will be here for the seventh vaccination.

For immune monitoring, blood is collected during the first injections and every 3 to 4 months thereafter. Immune cells (T cells and antigen-presenting cells) are isolated and incubated with peptides from the vaccination cocktail. T cells specifically activated by a peptide will be identified by intracellular cytokine staining and FACS analysis. The patient receives a report highlighting the vaccine peptides that induced a significant immune (T-cell) response. This information can in turn be used to control the immunogenicity of the vaccination regime and to further adjust the treatment plan.

From a clinical perspective, immune monitoring is the only way to monitor the immune system. It is also the only way to quantitatively gauge the efficacy of the vaccine therapy. This information is also critical for effectively timing and spacing the vaccine injections for maximum impact.

My Experience

The vaccine was painful; that’s really how I felt, and it was probably tolerated by many others!
That doesn’t mean that it stopped me from going :)
I used to get pain in some places more than others, so the doctor told me to pay attention to where the least number of pains was so we can schedule the next ones for (and I did follow that later, and that made a difference)
 
The side effects beyond the pain were that I used to get some (acceptable) fatigue a couple times during the day of treatment.  I also had bloating that lasted around 10 days for no reason (it did the same in the second and third visits)
 

Second Trip (6th Vaccination)

October 4th, 2021

The vaccine itself was a little painful.   However, I have had difficulties afterwards, as follows:

These were ones that I never had before (and never had afterwords in the following scheduled vaccines).

  • Around 1 PM:
    • So, during the first 30 minutes, I continued to have pain around the treatment location (7/10 of pain coming in and out).
  • Around 1:30 PM
    • After that, it came down to 5/10 pain and stayed for an extra
      hour.   After that (and until now), I couldn’t feel any pain
  • Around 2PM:
    • feeling chills (no fever): my hands stay continuously chills and I’m so cold, even if I am in a warm place.
  • Around 2:30:
    My whole body is in pain, almost everywhere
    • lack back pain
    • The back of chest pain
    • The back of knee pain
    • The back of neck pain
    • heel of foot pain
    • lost energy.
  • Around 3:00
    • Loss of energy (fatigue): It was difficult to stay standing (not
      enough power + feeling cold).  I had to sit to take
      rest.
  • Around 3:30
    • I had to run to the hotel and take a hot shower, which calmed down the “chill” feeling).
    • I decided to continue to be in bed for now.
    • The rest of the pain continues, but is reduced.  The remaining
      pain is focusing on the lower back (the rest is easier).

There is a list of things that I did not have at any point in time:

  • Headaches
  • Losing further focus
  • Seizures or auras
  • Sore throats

Dr. Buskup’s Response

The doctor believed that this was most certainly caused by the Leukine and the symptoms were acceptable and would get better next time.

The Next Visits

Third Trip (8th Vaccination)

November 12th, 2021

The vaccine was smooth, and I had no side effects of any sort (besides the annoying price of the vaccine itself).
 
She also decided to take the blood work that was scheduled in the following vaccine a bit earlier to see what the progress looked like given the last side effects of last time. I am expecting the outcome 4 weeks after this visit.
 

Fourth Trip (9th Vaccination)

December 9th, 2021

That day went without symptoms following the vaccine.   The doctor also took another blood test that day.
On that visit, the doctor told me that most likely the initial readings are inspiring her, that I won’t need to show them every month, and that she will confirm the readings further in 10 days or so (which I am sharing below).

December 18th, 2021

Less than two weeks after the trip, the doctor told me the following: “I have fantastic news for you! We can indeed switch to vaccinations every two months.
She then shared with me the Immune Monitoring Report (5 pages, sample taken on November 9th, 2021).   It states: “These results indicate that the administration of the vaccine successfully induced or at least enhanced specific CD4+ and CD8+ T-cell responses towards at least eight of the 19 vaccinated mutation-spanning peptides, among them responses towards two driver mutation-spanning peptides.  

January 4th, 2021

Please note that a brain MRI (without contrast) was just done (pointing to 1 year passing after the last brain surgery).
 
The outcome of the MRI Report said the following exact words “No significant changes could be seen to the previous study”

January 18th, 2021

I had Corona virus-positive (Omicron-BA.1).   I had a far better experience than the first time I had two years ago, and the most important symptom was a headache, which lasted for two days.

Fifth Trip (10th Vaccination)

February 16th, 2021

The vaccine went well, and I had no symptoms to complain about.
 
The doctor shared with me the newer Immune Monitoring Report (5 pages, sample taken on February 16th, 2022).   The results were even better than the last one that was shared in December 2021.
 
Yes, I had another immune-monitoring blood sample taken too.

6th, 7th and 8th Trips (11th, 12th and 13th vaccinations)

April 14th, September 22nd, and January 12th, 2023

During these last visits, I have been getting almost the same symtombs.  Dr. Buskup was quite busy during these visits, and I was not able to see her.
I met another great doctor, and I’ve learned from his side that, given that MRIs are not showing any progress, I should probably try other opportunities to take Ivosidenib and/or checkpoint inhibition.   I decided not to take any of these forward.
 
During my last trip in January 2023, I decided to put on hold taking further vaccines and learning what else to take forward given that I’m not seeing any cancer progress.   I was asked to take one (or two) more visits for an extra vaccine, but I felt I might decide to stop for a while.   The next 6 months or so that follow my last were engaging my time, including having relocated my location to live in Dubai, along with another minor surgery of percutaneous nephrolithotomy.
 
As I am planning to make a brain surgery, I am planning to take a sample for another pathology so we can evaluate the outcome and effectiveness of taking further vaccines matching the previous one, or to take a new variation if any further cancer outcome is shown.
 
 
 

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