AACR: A new way to enhance immunotherapy

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AACR: A new way to enhance immunotherapy

AACR: A new way to enhance immunotherapy.   Immunotherapy is a broad category of cancer treatment methods, including cell therapy, immune checkpoint inhibitors, vaccines, and immune system modulators.

Introduction:

The American Association of Cancer Research (AACR) was established in 1907. It was originally composed of 11 doctors and now has more than 42,000 members from 120 countries. Its purpose is to prevent and treat cancer through research, education, communication, cooperation, scientific policy and publicity, and funding for cancer research.

The AACR annual meeting is also the main forum for introducing and discussing cancer-related research. Each year the annual meeting attracts more than 20,000 participants from all over the world.

This year’s AACR21 will be held in two weeks, and the first week has just ended. The editor will take you to quickly browse some of the important topics of the annual meeting.

In the past decade, immunotherapy has brought revolutionary changes to cancer treatment, providing potential life-saving treatments for many patients with limited options. Although immunotherapy has been successful in many patients, there are still some challenges to overcome. Fortunately, new strategies to improve the efficacy of this therapy are still being developed and entered into clinical trials.

As the world’s premier cancer conference, the 2021 AACR Annual Conference held online on April 10-15 focused on some of the latest clinical developments in immunotherapy.

Immunotherapy is a broad category of cancer treatment methods, including cell therapy, immune checkpoint inhibitors, vaccines, and immune system modulators.

Certain immunotherapies, including cell-based therapies and some vaccines, are personalized treatments tailored to each patient’s cancer, but the customized manufacturing process takes time, and many patients do not have time.

Although immune checkpoint inhibitors do not require additional manufacturing time, many patients’ tumors do not qualify for these treatments. Cell-based therapies have successfully treated many hematological tumors, but have limited success in treating solid tumors.

Challenges associated with all forms of immunotherapy include lack of response in many patients (which may be due to the presence of immunological “cold” tumors) and the development of drug resistance (which may be due to depletion of T cells or loss of tumor antigens, And other reasons).

Several methods are currently being explored to overcome some of these obstacles. Researchers are evaluating various combination therapies to enhance response, and are working to develop “off-the-shelf” cell therapies so that patients can be treated more quickly.

In order to understand and prevent treatment of drug resistance, researchers are studying the basic mechanism of drug resistance, developing immunotherapy against multiple tumor antigens, and using CRISPR/Cas gene editing technology to delete an immune checkpoint from the patient’s immune cells protein. Changing the manufacturing process or the timing of treatment may also improve the response.

The clinical trials presented during the 2021 AACR annual meeting evaluated various strategies to enhance immunotherapy.

Ways to improve adaptive cell therapy

There are two characteristic trials that explore ways to enhance adaptive cell therapy, which is a cell-based immunotherapy in which the patient’s T cells are extracted, modified, proliferated, and regenerated in some cases. Introduced into the patient’s body. Adaptive cell therapy uses chimeric antigen receptor T (CAR T) cells or tumor infiltrating lymphocytes (TILs).

For CAR T cell therapy, the patient’s T cells are designed to express a chimeric antigen receptor (CAR) that binds to the antigen on the surface of cancer cells to activate anti-tumor immune signals. CAR-T therapy has achieved great success in treating some patients with hematological tumors. Currently, the United States has approved three CAR-T therapies for the treatment of certain lymphomas, and recently approved the first CAR-T therapy for multiple myeloma.

Although CAR T cell therapy is effective in some patients, the therapy has some limitations, including disease recurrence. For example, about half of B-cell lymphoma patients relapse within 6 months after initiating CAR T cell therapy because of the lack of persistence of CAR T cells and/or the downregulation of the target antigen CD19 on the tumor. Dr. Sanaz Ghafouri, a hematology and oncology researcher at the University of California, Los Angeles Medical Center, explained that patients who relapse after CAR T cell therapy face a dismal prognosis.

A potential strategy to reduce the risk of recurrence is to use bispecific CAR T cells, which target two tumor antigens at the same time. Ghafouri presented the results of a phase I clinical trial that used naive memory T cells to evaluate the safety and effectiveness of anti-CD19/CD20 bispecific CAR T cells.

The analysis of the study included 5 patients with B-cell malignant tumors. These patients had positive expression of CD19 and CD20 tumor antigens. Naive memory T cells are extracted from each patient, engineered to express anti-CD19/CD20 CAR, and expanded and then returned to the patient’s body.

After a median follow-up of 13 months, 4 out of 5 patients had sustained complete remission. At follow-up, the median progression-free and overall survival were not reached. At the time of the data cutoff, all patients who responded had CAR T cells persistently. All patients had grade 1 cytokine release syndrome. No dose-limiting toxicity or neurotoxicity associated with immune effector cells was observed. One death occurred a few months after CAR T cell treatment and was related to follow-up treatment.

“The bispecific CD19/CD20 CAR T cells exhibit excellent safety,” Ghafouri concluded. “Further analysis of more patients and longer follow-ups is needed to confirm these promising preliminary results.”

In another study published during the AACR annual meeting, researchers evaluated a new method for the treatment of TIL in patients with metastatic melanoma. This type of adaptive cell therapy relies on isolating TILs from patient tumors, then expanding them in vitro and reintroducing them into the patient.

Traditionally, only TILs with proven anti-tumor activity have been used. However, in this study, the researchers removed this selection step and instead harvested and expanded all the TILs contained in the excised tumor. In doing so, they can shorten the lengthy manufacturing process and allow a wide range of reactivity between the final TILs. Dr. Robert Hawkins, Chief Strategic Advisor of Instil Bio Inc. and Emeritus Professor/Consultant of Medical Oncology at the University of Manchester and Christie Hospital, said that by eliminating the selection step, additional neoantigen-reactive T cells that evade selection for various reasons can be captured and perfused.

In this retrospective analysis, Hawkins and colleagues assessed the safety and effectiveness of TIL therapy in 21 high-risk, metastatic melanoma patients who did not choose TIL therapy, who were based on sympathetic use after the previous treatment progressed. Received treatment. After a median follow-up time of 52.2 months, the objective response rate of all treated patients was 67%, of which 19% (4 out of 21) had a complete response. The median overall survival time was 21.3 months.

Adverse events related to the TIL regimen are consistent with those previously observed in patients receiving TILs for melanoma, including transient low blood counts, IL-2 related fever, tachycardia, stiffness and other symptoms.

“TIL products made from decomposing tumors have shown a high objective response rate in this sympathetic use program,” Hawkins said. “These results are worthy of further investigation in prospective clinical trials.” He pointed out that a global phase II clinical trial for patients with advanced melanoma is planned this year.

Explore methods for therapeutic cancer vaccines

Adaptive cell therapy relies on immune cell engineering to target cancer, while cancer vaccine is an immunotherapy that indirectly attacks cancer by training the patient’s immune cells to recognize and eliminate cancer cells.

Dr. Thomas Marron, assistant director of the “Early Stage and Immunotherapy Trials” at the Tisch Cancer Institute and assistant professor of medicine at Icahn School of Medicine, Mount Sinai, New York, explained that although most research personalized cancer vaccines are administered in a metastatic setting, However, more and more evidence shows that immunotherapy may be more effective if it is administered at an early stage when the patient’s tumor burden is lighter.

Therefore, Marron and colleagues reasoned that after standard care adjuvant treatment, when the patient’s residual disease is minimal, the administration of a personalized cancer vaccine may improve the efficacy. Marron presented the results of a phase I clinical trial evaluating this approach at a poster session during the AACR annual meeting.

Using the OpenVax computing pipeline, a personalized cancer vaccine (PGV-001) was developed for each patient participating in the study. The vaccine is based on the germline DNA, tumor DNA, tumor RNA sequence and human leukocyte antigen (HLA) type of each patient. Each patient’s personalized cancer vaccine includes up to 10 tumor neoantigen peptides, and uses tetanus auxiliary peptides to promote the patient’s immune response.

After surgery or autologous stem cell transplantation and any standard care adjuvant treatment, 13 patients received their own personalized PGV-001 vaccine and immunostimulant poly-ICLC. All patients received at least 7 doses of vaccine, and 11 patients received 10 doses of vaccine each.

After an average follow-up of 880 days, 4 patients had no evidence of disease, 4 patients were receiving follow-up treatment lines, 3 patients died, and 2 patients lost the opportunity for follow-up. The median progression-free survival was 618 days. The vaccine is well tolerated, with about half of patients experiencing a grade 1 injection site reaction.

Early results of ongoing immune surveillance showed that the treatment induced the expansion of CD4+ and CD8+ T cells specific to tumor neoantigen peptides. Two patients had a significant response to subsequent blockade of immune checkpoints.

“Our results show that the OpenVax pipeline is a viable method to generate a safe and personalized cancer vaccine that may be used to treat a range of tumor types,” Marron said at the AACR press conference.

In another report, Dr. Gregory Friedman, professor of pediatrics at the University of Alabama at Birmingham (UAB), discussed the results of a phase I clinical trial that evaluated a novel oncolytic virus therapy, a selective infection that uses a virus. And immunotherapy to destroy cancer cells. Since the resulting cancer cell fragments can trigger an anti-tumor immune response, the oncolytic virus can be said to be a cancer vaccine.

In this phase I clinical trial, Friedman and colleagues studied the safety and effectiveness of a modified herpes simplex virus type 1 (HSV-1) to treat pediatric brain cancer. It can be used alone or in combination with radiation therapy. Combine. Friedman explained that because HSV-1 naturally infects cells in the peripheral and central nervous system, brain tumors are an ideal target for this therapy. Genetic engineering is used to produce a modified HSV-1 (called G207) that can infect tumor cells but not normal cells.

The clinical trial included 12 high-grade glioma patients aged 7 to 18 who had tumor progression after previous treatment. G207 was injected into all 12 patients through an intratumoral catheter. Friedman explained that within 24 hours of the G207 infusion, some patients also received a single small dose of radiation against their tumors, the purpose of which is to enhance the replication of the virus and its spread throughout the tumor.

According to Friedman, a response was observed in 11 patients, with a median overall survival of 12.2 months—a 120% increase over the typical overall survival of advanced children with high-grade gliomas. G207 is well tolerated when used as a single agent or in combination with radiotherapy. There is no dose-limiting toxicity, grade 3/4 treatment-related adverse events, and no evidence of virus shedding into blood, saliva or conjunctiva.

In addition, the analysis of tumor tissues before and after treatment revealed that within 3 to 9 months after G207 perfusion, the number of tumor infiltrating immune cells increased, including CD4+ and CD8+ T cells. T cell infiltration was also observed several centimeters from the G207 inoculation site.

“These results show that this treatment method can transform immunologically’cold’ high gliomas in children with very few immune cells into’hot’ tumors with abundant immune cells, which is the development of effective immunotherapy for children’s brain tumors. A critical step.” Friedman said at the AACR press conference.

As these four studies have demonstrated, various immunotherapies for many cancer types and patient groups are being studied. Although immunotherapy still has some limitations to overcome, research is revealing new strategies to improve the efficacy of this revolutionary cancer treatment.

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