Therapeutic vaccine could improve checkpoint blockade efficacy for patients with cancer

Joshua Brody, MD
Joshua Brody

Researchers at Icahn School of Medicine at Mount Sinai have developed a novel vaccine that uses immune stimulants to inhibit cancer cell growth among patients with advanced-stage lymphoma.

“The in situ vaccine approach has broad implications for multiple types of cancer,” Joshua Brody, MD, physician in the department of hematology and medical oncology at Icahn School of Medicine at Mount Sinai, said in a press release. “This method could also increase the success of other immunotherapies, such as checkpoint blockade.”

The vaccine is being tested among patients with breast cancer and head and neck cancer.

HemOnc Today spoke with Brody about the rationale for this treatment approach, the efficacy observed in trials so far and additional research underway.

Question: What was the rationale for this treatment approach?

Answer: This is a way to increase the efficacy of checkpoint blockade ultimately, by teaching the immune system how to recognize patients’ tumor cells. This could potentiate checkpoint blockade therapy for our vast majority of patients for whom such therapy is not sufficiently effective.

Q: How was the study conducted?

A: Preclinical experiments in our lab allowed us to understand the cellular mechanisms of this immunotherapy. We then performed a clinical trial to prove the principles that we observed. The overall methods were to improve therapies, such as checkpoint blockades. Instead of going after those T cells that we think of as ‘immune soldiers,’ our focus has been to go upstream to the ‘generals’ of the immune army, the dendritic cells. Our 1-2-3 big concept is to recruit dendritic cells for the tumor, load those dendritic cells with tumor antigens, and activate those tumor antigen-loaded dendritic cells.

We accomplish this first with the protein hormone FL3TL. This hormone is used to recruit dendritic cells through injection into a tumor, then low-dose radiotherapy inhibits a few tumor cells to allow other antigens to fall out and be loaded onto those dendritic cells. At the end of this, what we have is a vaccine made at the tumor site in patients. When most hear the word, ‘vaccine,’ they may think of a prophylactic vaccine. But, this is a therapeutic vaccine to teach the immune system to recognize the cancer.

Q: Can you elaborate on what you found?

A: Results of animal models showed that we could induce antitumor T cells that could inhibit tumor growth — both at the injected site and at distant sites. We were able to cure about 40% of mice with this in situ vaccine, and the cure rate went up to 80% when we added the checkpoint blockade anti-PD-1 antibodies. Among the 11 patients we treated, we observed regression in some patients with bulky tumors that yielded systemic partial and complete remissions, which lasted months to years.

Q: What should clinicians take away from this?

A: Because the vaccine works well among patients with lymphoma, and was greatly potentiated by checkpoint blockade in the lab, we opened the version 2.0 clinical trial NCT03789097. We are combining the vaccine and an anti-PD-1 therapy in this trial for patients with lymphoma, breast cancer, or head and neck cancer. We have already started treating patients and are extremely optimistic that we are going to see great results in this ongoing trial. We hope to have preliminary results 1 year from now.

Q: When do you anticipate that we will see this treatment used in practice?

A: We are already using some intratumoral immune stimulants in clinical practice. The only FDA approval of this so far is with the virus talimogene laherparepvec, or T-VEC (Imlygic, Amgen), and that approval is only for local-stage disease, not metastatic disease. Speaking broadly for in situ vaccines, we have extremely promising phase 2-and-beyond trials of other intratumoral toll-like receptor agonists, which could be FDA-approved within a couple of years. – by Jennifer Southall

Reference:

Hammerich L, et al. Nat Med. 2019;doi:10.1038/s41591-019-0410-x.

For more information:

Joshua D. Brody, MD, can be reached at Icahn School of Medicine at Mount Sinai, 1470 Madison Ave., New York, NY 10029; email: joshua.brody@mssm.edu.

Disclosure: Brody reports no relevant financial disclosures. The study was funded by the Damon Runyon Cancer Research Foundation, the Cancer Research Institute and Merck. Celldex and Oncovir provided reagents for the clinical trial and the lab work.

Joshua Brody, MD
Joshua Brody

Researchers at Icahn School of Medicine at Mount Sinai have developed a novel vaccine that uses immune stimulants to inhibit cancer cell growth among patients with advanced-stage lymphoma.

“The in situ vaccine approach has broad implications for multiple types of cancer,” Joshua Brody, MD, physician in the department of hematology and medical oncology at Icahn School of Medicine at Mount Sinai, said in a press release. “This method could also increase the success of other immunotherapies, such as checkpoint blockade.”

The vaccine is being tested among patients with breast cancer and head and neck cancer.

HemOnc Today spoke with Brody about the rationale for this treatment approach, the efficacy observed in trials so far and additional research underway.

Question: What was the rationale for this treatment approach?

Answer: This is a way to increase the efficacy of checkpoint blockade ultimately, by teaching the immune system how to recognize patients’ tumor cells. This could potentiate checkpoint blockade therapy for our vast majority of patients for whom such therapy is not sufficiently effective.

Q: How was the study conducted?

A: Preclinical experiments in our lab allowed us to understand the cellular mechanisms of this immunotherapy. We then performed a clinical trial to prove the principles that we observed. The overall methods were to improve therapies, such as checkpoint blockades. Instead of going after those T cells that we think of as ‘immune soldiers,’ our focus has been to go upstream to the ‘generals’ of the immune army, the dendritic cells. Our 1-2-3 big concept is to recruit dendritic cells for the tumor, load those dendritic cells with tumor antigens, and activate those tumor antigen-loaded dendritic cells.

We accomplish this first with the protein hormone FL3TL. This hormone is used to recruit dendritic cells through injection into a tumor, then low-dose radiotherapy inhibits a few tumor cells to allow other antigens to fall out and be loaded onto those dendritic cells. At the end of this, what we have is a vaccine made at the tumor site in patients. When most hear the word, ‘vaccine,’ they may think of a prophylactic vaccine. But, this is a therapeutic vaccine to teach the immune system to recognize the cancer.

Q: Can you elaborate on what you found?

A: Results of animal models showed that we could induce antitumor T cells that could inhibit tumor growth — both at the injected site and at distant sites. We were able to cure about 40% of mice with this in situ vaccine, and the cure rate went up to 80% when we added the checkpoint blockade anti-PD-1 antibodies. Among the 11 patients we treated, we observed regression in some patients with bulky tumors that yielded systemic partial and complete remissions, which lasted months to years.

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Q: What should clinicians take away from this?

A: Because the vaccine works well among patients with lymphoma, and was greatly potentiated by checkpoint blockade in the lab, we opened the version 2.0 clinical trial NCT03789097. We are combining the vaccine and an anti-PD-1 therapy in this trial for patients with lymphoma, breast cancer, or head and neck cancer. We have already started treating patients and are extremely optimistic that we are going to see great results in this ongoing trial. We hope to have preliminary results 1 year from now.

Q: When do you anticipate that we will see this treatment used in practice?

A: We are already using some intratumoral immune stimulants in clinical practice. The only FDA approval of this so far is with the virus talimogene laherparepvec, or T-VEC (Imlygic, Amgen), and that approval is only for local-stage disease, not metastatic disease. Speaking broadly for in situ vaccines, we have extremely promising phase 2-and-beyond trials of other intratumoral toll-like receptor agonists, which could be FDA-approved within a couple of years. – by Jennifer Southall

Reference:

Hammerich L, et al. Nat Med. 2019;doi:10.1038/s41591-019-0410-x.

For more information:

Joshua D. Brody, MD, can be reached at Icahn School of Medicine at Mount Sinai, 1470 Madison Ave., New York, NY 10029; email: joshua.brody@mssm.edu.

Disclosure: Brody reports no relevant financial disclosures. The study was funded by the Damon Runyon Cancer Research Foundation, the Cancer Research Institute and Merck. Celldex and Oncovir provided reagents for the clinical trial and the lab work.

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