Peptide-based Vaccine for Myeloproliferative Disorders

Overseen By Gabriela Bello

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Michal Bar-Natan

Must not be taking: Immunosuppressants, Steroids, Ruxolitinib, others

Disqualifiers: Autoimmune disease, Immunodeficiency, Infection, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 1

Duration: 32 weeks

10 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new vaccine to determine its safety and tolerability for individuals with certain myeloproliferative disorders, where bone marrow cells grow abnormally. The focus is on patients with myelofibrosis or essential thrombocythemia who have a specific mutation in their CALR gene. The Mutant CALR-peptide Based Vaccine targets this mutation. Suitable participants should have one of these conditions and have tried other treatments. The study includes tests, such as bone marrow biopsies, and will take place at The Mount Sinai Hospital. As a Phase 1 trial, the research aims to understand how the treatment works in people, offering participants the chance to be among the first to receive this new vaccine.

Do I need to stop my current medications to join the trial?

Yes, you will need to stop taking certain medications, including immunosuppressive drugs, steroids, Ruxolitinib, Fedratinib, hydroxyurea, and INF. However, the use of anagrelide is allowed.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research shows that the mutant CALR-peptide vaccine is generally safe and well-tolerated. Studies have found that similar vaccines using small proteins from mutant CALR, combined with montanide, are safe. These studies reported no serious safety issues, suggesting that patients receiving the vaccine experience few, if any, side effects. While this is encouraging, it's important to note that this trial is in an early stage. The researchers are primarily focused on understanding the vaccine's safety in humans. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for myeloproliferative disorders, which often include medications like hydroxyurea or interferon alpha, the Mutant CALR-peptide Based Vaccine works by specifically targeting CALR mutations found in some patients with myelofibrosis and essential thrombocythemia. This vaccine approach is unique because it uses peptides to stimulate the immune system to recognize and attack cancer cells with these mutations. Researchers are excited about this treatment because it offers a more personalized approach, potentially leading to fewer side effects and improved effectiveness for patients with this specific genetic mutation.

What evidence suggests that this treatment might be an effective treatment for myeloproliferative disorders?

Research shows that the mutant CALR-peptide vaccine, which participants in this trial will receive, could be a promising treatment for myeloproliferative disorders, particularly those with CALR mutations. Previous studies found that this vaccine is safe and well-tolerated when combined with substances that enhance the immune system's response. This suggests the vaccine might help the immune system identify and combat abnormal cells in these disorders. While more information is needed to confirm its effectiveness, the vaccine targets common mutations in these conditions. Early results are promising, and ongoing research will offer more insights into its potential benefits. ^{1 2 3 6 7}

Who Is on the Research Team?

Marina Kremyanskaya

Principal Investigator

Icahn School of Medicine at Mount Sinai

Nina Bhardwaj, MD, PhD

Principal Investigator

Icahn School of Medicine at Mount Sinai

Camelia Iancu-Rubin, PhD

Principal Investigator

Icahn School of Medicine at Mount Sinai

Are You a Good Fit for This Trial?

This trial is for adults over 18 with certain types of myeloproliferative neoplasms (MPNs) who have a specific CALR mutation. Participants need normal organ function, no recent other cancers except some localized ones, and can't be on certain medications or have serious infections or autoimmune diseases. They must use effective birth control if applicable.

Inclusion Criteria

I am committed to using two forms of birth control and agree to regular pregnancy tests if I can become pregnant. If I am a man, I will use a condom.

I have a confirmed chronic MPN and am considered high risk or low-intermediate risk.

Creatinine ≤ 2.5 mg/dL

Exclusion Criteria

Treatment with other experimental drugs

I am currently taking Ruxolitinib or Fedratinib.

I am currently taking hydroxyurea.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive the mutated-CALR peptide vaccine to assess safety and tolerability

32 weeks

Regular visits for vaccine administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

48 weeks

Periodic visits for assessment and lab tests

Long-term follow-up

Participants are monitored for long-term outcomes and adverse events

80 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Mutant CALR-peptide Based Vaccine

Trial Overview The study tests the safety of a mutated-CALR peptide vaccine in MPN patients at The Mount Sinai Hospital. Over 80 weeks, participants will receive the vaccine along with Poly ICLC adjuvant, complete questionnaires, undergo bone marrow biopsies and lab collections.

How Is the Trial Designed?

Group I: CALR mutated Experimental Treatment 2 Interventions

peptide-based vaccine in patients with myeloproliferative neoplasm (myelofibrosis and essential thrombocythemia) with CALR mutations

Who Is Running the Clinical Trial?

Michal Bar-Natan

Lead Sponsor

Trials

1

Recruited

10+

Marina Kremyanskaya

Lead Sponsor

Trials

2

Recruited

10+

Published Research Related to This Trial

Peptide vaccination is a promising strategy to activate T-cells against specific antigens in blood cancers, targeting both classical tumor-associated antigens and new neo-antigens like JAK2 and CALR mutations.

Clinical trials are underway for peptide vaccines in various hematological malignancies, including myelodysplastic syndromes and multiple myeloma, highlighting their potential to enhance immune responses in challenging tumor microenvironments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel Strategies for Peptide-Based Vaccines in Hematological Malignancies. Klausen, U., Holmberg, S., Holmström, MO., et al.[2023]

CALR mutations are common in patients with chronic myeloproliferative neoplasms (MPN), and this study found that both healthy individuals and CALR wild-type (CALRwt) MPN patients have spontaneous immune responses to these mutations.

Healthy individuals showed stronger and more frequent T-cell responses against CALR mutations compared to CALR-mutant MPN patients, suggesting that the immune system in healthy people can recognize and potentially eliminate cells with CALR mutations, contributing to tumor immune surveillance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High frequencies of circulating memory T cells specific for calreticulin exon 9 mutations in healthy individuals. Holmström, MO., Ahmad, SM., Klausen, U., et al.[2021]

Patients with CALR-mutated myeloproliferative neoplasms (MPNs) have a low frequency of T cells that respond to CALRMUT neoantigens due to underrepresentation of MHC-I alleles that present these antigens effectively, suggesting a potential immune evasion mechanism.

Immunization with modified heteroclitic CALRMUT peptides tailored to the MHC-I alleles of these patients successfully elicited a strong CD8+ T cell response, indicating that heteroclitic peptide-based cancer vaccines could be a promising therapeutic strategy for CALRMUT MPN.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Calreticulin mutant myeloproliferative neoplasms induce MHC-I skewing, which can be overcome by an optimized peptide cancer vaccine. Gigoux, M., Holmström, MO., Zappasodi, R., et al.[2023]

The phase I clinical trial involving 10 patients with CALR-mutant chronic myeloproliferative neoplasms demonstrated that the CALRLong36 peptide vaccine was safe and well-tolerated, with only two grade three adverse events reported, none related to the vaccine.

While the vaccine did not lead to clinical responses, a significant T-cell immune response was observed in the majority of patients, suggesting potential for combining this vaccination approach with other cancer therapies to enhance anti-tumor effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic Cancer Vaccination With a Peptide Derived From the Calreticulin Exon 9 Mutations Induces Strong Cellular Immune Responses in Patients With CALR-Mutant Chronic Myeloproliferative Neoplasms. Handlos Grauslund, J., Holmström, MO., Jørgensen, NG., et al.[2022]

Therapeutic cancer vaccination targeting mutant calreticulin (CALR) in patients with CALR-mutant myeloproliferative neoplasms did not lead to an increase in CALRmut specific T cells in the bone marrow after vaccination, indicating a lack of clinical activity despite strong T-cell responses.

The study found a significant imbalance between the number of transformed CALRmut cells and the CALRmut specific effector T cells in peripheral blood, which may hinder the ability of these T cells to migrate and enrich in the bone marrow.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic cancer vaccination against mutant calreticulin in myeloproliferative neoplasms induces expansion of specific T cells in the periphery but specific T cells fail to enrich in the bone marrow. Holmström, MO., Andersen, M., Traynor, S., et al.[2023]

CALR exon 9 mutations, found in about 30% of patients with essential thrombocythemia and primary myelofibrosis, can be specifically recognized by T cells, indicating a potential target for immune therapy.

The study established that CALR-mutant-specific CD4+ T cells can effectively kill CALR-mutant cells, suggesting that these mutations could be used for developing peptide vaccinations to enhance cancer treatment in affected patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The calreticulin (CALR) exon 9 mutations are promising targets for cancer immune therapy. Holmström, MO., Martinenaite, E., Ahmad, SM., et al.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05025488

NCT05025488 | Mutant CALR-peptide Based Vaccine in ... The primary objective of this study is to assess the safety and tolerability of administrating mutated-CALR peptide Vaccine to patients with MPN.

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/33718228/

Therapeutic Cancer Vaccination With a Peptide Derived ... Conclusion: Therapeutic cancer vaccination with peptide vaccines derived from mutant CALR with montanide as an adjuvant, is safe and tolerable.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT03566446

NCT03566446 | CALR Exon 9 Mutant Peptide Vaccine to ... In December 2013 two independent research groups reported on the occurrence of somatic mutations in exon 9 of the calreticulin gene in patients with ET and PMF.

4. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2023-03541

Mutant-CALR Peptide Vaccine for the Treatment of Patients ... This phase I trial tests the safety and effectiveness of a mutant-calreticulin (CALR) peptide vaccine given with keyhole limpet hemocyanin (KLH) and poly-ICLC

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7952976/

Therapeutic Cancer Vaccination With a Peptide Derived From ... Conclusion. Therapeutic cancer vaccination with peptide vaccines derived from mutant CALR with montanide as an adjuvant, is safe and tolerable.

6. mountsinai.org mountsinai.org/clinical-trials/mutant-calr-peptide-based-vaccine-in-patients-with-mutated-calr-myeloproliferative-neoplasm

Mutant CALR-peptide Based Vaccine in Patients With ... The primary objective of this study is to assess the safety and tolerability of administrating mutated-CALR peptide Vaccine to patients with MPN.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10470021/

Therapeutic cancer vaccination against mutant calreticulin ... The vaccines consisted of a peptide (CALRLong36) derived from the mutant CALR C-terminus with montanide as an adjuvant. The vaccines were safe ...