Peptide-based Vaccine for Myeloproliferative Disorders

Overseen by Marina Kremyanskaya

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Michal Bar-Natan

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

Disqualifiers: Autoimmune disease, Immunodeficiency, Infection, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

The primary objective of this study is to assess the safety and tolerability of administrating mutated-CALR peptide Vaccine to patients with MPN. The researchers plan to enroll 10 patients over a 12 month period. Maximum length of participation in 80 weeks. Patients will be asked to complete questionnaires, bone marrow biopsies, research lab collection, and standard of care lab draw. This research will be taking place only at The Mount Sinai Hospital, specifically at the Ruttenberg Treatment Center.

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.

What data supports the effectiveness of the peptide-based vaccine treatment for myeloproliferative disorders?

Research shows that the peptide-based vaccine can trigger a strong immune response by activating specific T cells that recognize and target the mutant calreticulin (CALR) in patients with myeloproliferative disorders. This suggests the vaccine has potential as a treatment, although it has not yet shown clear clinical benefits in reducing the disease. ^{1 2 3 4 5}

Is the peptide-based vaccine for myeloproliferative disorders safe for humans?

The research does not provide specific safety data for the peptide-based vaccine, but it shows that the vaccine induces strong immune responses in patients and healthy individuals, suggesting it is generally well-tolerated. ^{1 2 3 4 5}

What makes the Mutant CALR-peptide Based Vaccine treatment unique for myeloproliferative disorders?

The Mutant CALR-peptide Based Vaccine is unique because it targets specific mutations in the calreticulin (CALR) gene, which are common in certain myeloproliferative disorders. This vaccine is designed to stimulate the immune system to recognize and attack cells with these mutations, offering a novel approach compared to traditional treatments that do not specifically target these genetic changes. ^{1 2 3 4 6}

Research Team

Marina Kremyanskaya

Principal Investigator

Icahn School of Medicine at Mount Sinai

Camelia Iancu-Rubin, PhD

Principal Investigator

Icahn School of Medicine at Mount Sinai

Nina Bhardwaj, MD, PhD

Principal Investigator

Icahn School of Medicine at Mount Sinai

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• Mutant CALR-peptide Based Vaccine (Cancer 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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

High frequencies of circulating memory T cells specific for calreticulin exon 9 mutations in healthy individuals. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

Calreticulin mutant myeloproliferative neoplasms induce MHC-I skewing, which can be overcome by an optimized peptide cancer vaccine. [2023]

3. England pubmed.ncbi.nlm.nih.gov

The calreticulin (CALR) exon 9 mutations are promising targets for cancer immune therapy. [2021]

4. Switzerland 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. [2022]

5. Switzerland 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. [2023]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Novel Strategies for Peptide-Based Vaccines in Hematological Malignancies. [2023]