Meeting News CoveragePerspective

CD4 T-cell immunotherapy that targets MAGE-A3 shows promise in metastatic cancer

NEW ORLEANS — An immunotherapy that uses genetically engineered CD4 T cells to target the MAGE-A3 protein in cancer cells safely treated patients with metastatic cancers, according to data presented at the American Association for Cancer Research Annual Meeting.

The treatment also induced clinical responses in certain patients.

“Our study expands the number of patients with cancer potentially suitable for treatment with immunotherapy approaches,” Steven A. Rosenberg, MD, PhD, chief of the surgery branch at the NCI Center for Cancer Research, told HemOnc Today. “This trial is helping to define the role of CD4 T cells in cancer immunotherapy.”

Steven Rosenberg

Steven A. Rosenberg

Research suggests that CD4–positive T cells can induce tumor regression in patients with metastatic cancers, with an effect similar to that seen with CD8–positive T cells, according to study background.

HLA-DPB1*0401 is present in more than 60% of non-Hispanic white individuals, and MAGE-A3 is expressed in up to one-third of tumor specimens across cancer subtypes, leading the researchers to believe that T-cell receptor (TCR) immunotherapy may be used to treat many types of cancer.

The researchers tested this hypothesis by isolating an HLA-DPB1*0401–restricted TCR recognizing MAGE-A3 from a patient’s peripheral blood, following a MAGE-A3 peptide vaccination.

The analysis included data from 14 HLA-DPB1*0401–positive patients with MAGE-A3–positive tumor specimens who did not respond to or relapsed after one standard first-line therapy for their cancer.

Patients received a lymphodepleting preparative regimen, followed by the adoptive transfer of purified CD4–positive T cells transduced with HLA-DPB1*0401–restricted MAGE-A3 TCR and systemic high-dose interleukin-2.

The researchers evaluated escalating cell doses. The first eight patients were treated at different dose levels ranging from 1 million to 30 billion cells. The last six patients received doses ranging from 78 billion to 103 billion.

Three patients achieved objective partial responses by RECIST criteria: one with metastatic cervical cancer (ongoing for more than 11 months), one patient with esophageal cancer (duration, 3 months) and one patient with urothelial cancer (ongoing for more than 4 months).

All patients had highly detectable levels of interleukin-6 in their serum samples following the adoptive cell transfer.

TCR–transduced T cells persisted at high levels in the peripheral blood of the six patients who received the highest dose level 1 month after treatment, compared with patients who received lower dose levels (P = .0082).

All but two patients developed a high but transient fever during treatment. One patient experienced grade 3 toxicity, with liver and renal injury; however, the researchers did not believe this was treatment-related.

“We are studying the clinical responses of patients with different types of metastatic cancers in an ongoing phase 2 trial,” Rosenberg said. – by Cameron Kelsall

For more information:

Steven A. Rosenberg, MD, PhD, can be reached at sar@nih.gov.

Reference:

Lu YC, et al. Abstract CT003. Presented at: American Association for Cancer Research Annual Meeting; April 16-20, 2016; New Orleans.

Disclosure: The Intramural Research program of the NIH funded this study. The NCI’s research and development of T-cell receptor therapy used in this study was funded through a cooperative research and development agreement between the NCI and Kite Pharma, with Kite Pharma holding an exclusive worldwide license for the intellectual property used in this study. Rosenberg reports no relevant financial disclosures.

NEW ORLEANS — An immunotherapy that uses genetically engineered CD4 T cells to target the MAGE-A3 protein in cancer cells safely treated patients with metastatic cancers, according to data presented at the American Association for Cancer Research Annual Meeting.

The treatment also induced clinical responses in certain patients.

“Our study expands the number of patients with cancer potentially suitable for treatment with immunotherapy approaches,” Steven A. Rosenberg, MD, PhD, chief of the surgery branch at the NCI Center for Cancer Research, told HemOnc Today. “This trial is helping to define the role of CD4 T cells in cancer immunotherapy.”

Steven Rosenberg

Steven A. Rosenberg

Research suggests that CD4–positive T cells can induce tumor regression in patients with metastatic cancers, with an effect similar to that seen with CD8–positive T cells, according to study background.

HLA-DPB1*0401 is present in more than 60% of non-Hispanic white individuals, and MAGE-A3 is expressed in up to one-third of tumor specimens across cancer subtypes, leading the researchers to believe that T-cell receptor (TCR) immunotherapy may be used to treat many types of cancer.

The researchers tested this hypothesis by isolating an HLA-DPB1*0401–restricted TCR recognizing MAGE-A3 from a patient’s peripheral blood, following a MAGE-A3 peptide vaccination.

The analysis included data from 14 HLA-DPB1*0401–positive patients with MAGE-A3–positive tumor specimens who did not respond to or relapsed after one standard first-line therapy for their cancer.

Patients received a lymphodepleting preparative regimen, followed by the adoptive transfer of purified CD4–positive T cells transduced with HLA-DPB1*0401–restricted MAGE-A3 TCR and systemic high-dose interleukin-2.

The researchers evaluated escalating cell doses. The first eight patients were treated at different dose levels ranging from 1 million to 30 billion cells. The last six patients received doses ranging from 78 billion to 103 billion.

Three patients achieved objective partial responses by RECIST criteria: one with metastatic cervical cancer (ongoing for more than 11 months), one patient with esophageal cancer (duration, 3 months) and one patient with urothelial cancer (ongoing for more than 4 months).

All patients had highly detectable levels of interleukin-6 in their serum samples following the adoptive cell transfer.

TCR–transduced T cells persisted at high levels in the peripheral blood of the six patients who received the highest dose level 1 month after treatment, compared with patients who received lower dose levels (P = .0082).

All but two patients developed a high but transient fever during treatment. One patient experienced grade 3 toxicity, with liver and renal injury; however, the researchers did not believe this was treatment-related.

“We are studying the clinical responses of patients with different types of metastatic cancers in an ongoing phase 2 trial,” Rosenberg said. – by Cameron Kelsall

For more information:

Steven A. Rosenberg, MD, PhD, can be reached at sar@nih.gov.

Reference:

Lu YC, et al. Abstract CT003. Presented at: American Association for Cancer Research Annual Meeting; April 16-20, 2016; New Orleans.

Disclosure: The Intramural Research program of the NIH funded this study. The NCI’s research and development of T-cell receptor therapy used in this study was funded through a cooperative research and development agreement between the NCI and Kite Pharma, with Kite Pharma holding an exclusive worldwide license for the intellectual property used in this study. Rosenberg reports no relevant financial disclosures.

    Perspective
    Hossein Borghaei

    Hossein Borghaei

    The fact that CD4 cells can be directed to tumors and that this approach can lead to responses for some patients is encouraging. The treatment also appears to be safe, although more data on the kind of toxicities seen are needed.

    This treatment is, at this point, available only to patients with a specific HLA subtype, which is found in up to 60% of non-Hispanic white patients, according to the researchers.

    The remaining issues here are the preparation time for such an approach and how to make it available to more patients. Manufacturing of T cells in this fashion is still a rather limiting step. As the field is moving forward, this may become less of an issue, but I dont think were there yet.

    The need for HLA matching suggests that this kind of treatment needs to be directed at specific individuals. This last point is fine, given we have molecularly targeted therapies that are only effective and available in certain patients. 

    This is nice progress, and scientifically significant. However, a lot remains to be seen from a clinical standpoint. The data are encouraging, but it is too early to tell how successful it will be. 

    • Hossein Borghaei, DO
    • Fox Chase Cancer Center

    Disclosures: Borghaei reports consultant roles with Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Clovis Oncology, Genentech, Lilly Oncology and Pfizer.

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