Promising Results in Stage 3-4 Kidney Cancer with a New Personalized Cancer Vaccine

The most common subtype of kidney cancer, clear cell renal cell carcinoma (ccRCC), carries a high risk of recurrence at advanced stages (Stages III and IV). Standard treatment includes surgical removal of the tumor followed by immunotherapy with immune checkpoint inhibitors such as pembrolizumab. However, the disease may recur in 67% of these patients, and existing treatment options are limited.

A new study led by the Dana-Farber Cancer Institute and published on February 5 in Nature showed that a personalized cancer vaccine administered after surgery produced a strong anticancer immune response in patients and could prevent disease recurrence.

What Is a Personalized Neoantigen Cancer Vaccine?

A neoantigen cancer vaccine is a personalized cancer treatment specifically designed using molecular markers obtained from each patient's own tumor.

Neoantigensare mutated protein fragments found in cancer cells but not in normal cells. By identifying these neoantigens, researchers developed a customized vaccine that trains the immune system to target the tumor.

The vaccine was administered to patients after surgery as a series of initial doses, followed by two booster doses. This new approach aims to enable the body to recognize and destroy remaining tumor cells.

How the NeoVax Cancer Vaccine Works and Is Manufactured

NeoVax is a personalized cancer vaccine manufactured using genetic and molecular information obtained from each patient's tumor tissue. The process consists of the following steps:

1. Tumor Tissue Collection and Analysis:

   • Tumor tissue removed from the patient during surgery is analyzed.

   • Mutations that distinguish tumor cells from normal cells are identified.

2. Identification of Neoantigens:

   • Genetic analyses and bioinformatics algorithms are used to identify neoantigens specific to cancer cells.

   • These neoantigens are selected as targets against which the immune system can mount a strong response.

3. Preparation of Vaccine Components:

   • The selected neoantigens are manufactured as synthetic peptides.

   • These peptides are combined with suitable carrier molecules to activate the immune system.

   • The vaccine is formulated to enable the patient's immune system to target tumor cells specifically.

4. Administration of the Vaccine to the Patient:

   • The vaccine is administered to the patient by subcutaneous or intramuscular injection.

   • The vaccine is given in several doses, with booster doses administered at specified intervals.

5. Monitoring the Immune Response:

   • The immune response of vaccinated patients is monitored regularly.

   • Blood samples are collected to measure T-cell activity and numbers.

   • The resulting immune response is assessed to determine whether the remaining tumor cells have been eliminated.

FIGURE: Manufacturing and Administration of a Neoantigen-Targeted Personalized Cancer Vaccine (PCV) for Clear Cell Renal Cell Carcinoma (ccRCC)

a. Design and Administration of the Neoantigen-Targeted Cancer Vaccine

This diagram shows the design and administration of the personalized cancer vaccine (PCV) developed for ccRCC.

• Tumor Sample: Tumor samples from patients with Stage III-IV RCC were used.
• Genetic Analysis: Whole-exome sequencing (WES) and RNA sequencing (RNA-seq) of tumor samples were used to predict neoantigens (using HLAthena).
• Target Selection: Up to 20 personalized neoantigens were identified.
• Vaccine Manufacturing: Pools of synthetic long peptides specific to the neoantigens were produced.
• Vaccine Administration: The vaccine was administered with poly-ICLC (an immune response enhancer).
• Half of the vaccine was given subcutaneously (under the skin), and the other half intradermally (between the layers of the skin).
• Some patients also received subcutaneous ipilimumab immunotherapy.
• Blood Sample Collection: Blood samples were collected at specified time points over 24 weeks (indicated by red arrows).

b. Vaccine Manufacturing and Neoantigen Selection

This chart summarizes the vaccine manufacturing process:

• Top Chart: The number of high-quality coding mutations found in each tumor.
• Middle Chart: The number of neoantigen vaccine peptides administered to patients.
• Bottom Chart: RCC-specific driver mutations targeted by the vaccine. These include mutations in genes such as PIK3CA, VHL, BAP1, KDM5G, KDM5C, and PBRM1.
• SNVs (single-nucleotide variants) and frameshift mutations are shown separately by mutation type.

c. Patient Follow-up (Swimmer's Plot)

This chart shows each patient's follow-up and clinical status after nephrectomy:

• Bars: Show patients' postoperative follow-up durations.
• Colors: Indicate whether patients had Stage III or IV disease.
• Symbols:
  • Square (■): Start of vaccine administration.
  • Triangle (△): Booster vaccine dose.
  • Arrows (→): Indicate that the patient is alive and has no signs of disease.
  • Plus (✚): Death from an unrelated cause, with no signs of disease at the last follow-up.

d. Disease-Free Survival (Kaplan–Meier Curve)

This Kaplan–Meier survival analysis shows disease-free survival rates from administration of the first vaccine dose onward.

• X-Axis: Time since the first vaccination (months).
• Y-Axis: Disease-free survival rate.
• Red Line: Shows disease-free survival over time in the patients followed.
• Numbers at the Bottom: Show the number of people at risk.

This study was conducted to assess the potential of personalized cancer vaccines to prevent disease recurrence in patients with RCC.

Details and Results of the Nature Study

This early-stage (phase I) clinical trial evaluated nine patients diagnosed with Stage III or IV ccRCC whose tumors had been surgically removed. Five of these patients received ipilimumab (another immune checkpoint inhibitor) along with the vaccine.

The most striking results:

• 34.7 months after follow-up began, all patients remained disease-free (there was no cancer recurrence).

• The vaccine activated patients' immune systems within 3 weeks and was capable of increasing T cells strongly associated with cancer 166-fold .

• T-cell levels remained high for up to 3 years after disease onset.

• The vaccine was shown to induce a specific immune response against cancer cells .

• An immune response was detected in all patients, and in seven patients, the vaccine was observed to act against specific gene mutations associated with the cancer process (such as VHL, PBRM1, and BAP1).

• No serious adverse effects were observed; adverse effects were limited to local skin reactions and flu-like symptoms .

Conclusion and Future Perspectives

The results of this study are very promising; the vaccine could offer an effective treatment option for tumors with a low mutational burden, such as kidney cancer.

This personalized vaccine approach had also previously been successful in cancers with a high mutational burden, such as melanoma. However, this study demonstrated that it could also be effective in cancers with fewer mutations, such as ccRCC.

Another personalized cancer vaccine, code-named V940 and also known as mRNA-4157 , is being studied in a large-scale, international, randomized phase II trial (NCT06307431) as adjuvant treatment in combination with pembrolizumab.

If these advanced trials are also successful, personalized cancer vaccines could become a new standard treatment option for kidney cancer and other tumors with a low mutational burden.