AACR Annual Meeting 2016

CD4+ T cells genetically engineered to recognize MAGE-A3, a protein found on many types of tumor cells but not on normal cells, were safely given to patients with metastatic cancers, and some of the patients had clinical responses.

Whereas the majority of current adoptive T-cell therapies have used genetically modified unpurified T cells or CD8+ (cytotoxic) T cells, Yong-Chen William Lu, Ph.D., of the surgery branch of the National Cancer Institute conducted a phase I trial of CD4+ (helper) T cells to evaluate their contribution to tumor killing. Preclinical and clinical studies indicated that CD4+ T cells can induce tumor regression.

Dr. Lu explained the individualized process of making the T cells for infusion, during a news conference at the annual meeting of the American Association for Cancer Research. First, T cells are harvested from the peripheral blood of a patient, from which CD4+ T cells are isolated. Using a retroviral vector, scientists insert the gene for a T-cell receptor that recognizes MAGE-A3 in conjunction with the HLA molecule DPB1*0401. In this way, the cells can recognize the tumor antigen in anyone of that HLA type. Then the cells carrying the engineered T-cell receptor are expanded in vitro and infused into the patient.

DPB1*0401 was chosen as the HLA genotype because “it is present in 60% of the Caucasian population. It is the highest one,” Dr. Lu said. MAGE-A3 is expressed on cells during fetal development and is later lost on normal tissues. But several tumor types, including some melanomas and some urothelial, esophageal, and cervical cancers reexpress this protein, making it a good target for immunotherapy.

The trial included patients of the HLA DPB1*0401 type with metastatic cancer that is MAGE-A3 positive. Patients had received at least one first-line treatment for metastatic disease and had been nonresponders or had had a recurrence of the tumor.

This phase I trial involved 14 patients in nine different dose cohorts, receiving from 10 million engineered T cells at the lowest dose to 78-103 billion cells in the highest cohort. Three patients in the middle and highest dosing cohorts achieved partial responses, one each with cervical, esophageal, and urothelial tumors. The partial response lasted 4 months for the patient with esophageal cancer and is ongoing at 7 months for the urothelial and 15 months for the cervical cancer patients.

In response to a question from the audience about adverse effects, Dr. Lu said patients had short-term elevations of circulating cytokines, “which only lasted for a few days,” and a fever lasting 1-2 weeks.

In summary, he said, “We think this first [CD4+] engineered T-cells therapy targeting MAGE-A3 is safe and has shown early clinical response.” Phase II trials are now beginning.

The approach of this immunotherapy method is different from that involved in using checkpoint inhibitors, “which essentially release the brakes of the immune system so the T cells can do their job of attacking the cancer,” commented Dr. Louis Weiner, director of the Georgetown Lombardi Cancer Center in Washington, D.C. “This is actually not trying to release brakes but essentially press on the accelerator, if you will, by using an expanded tumor-specific population of T cells that will then be able to hone in and attack the cancer.” He envisioned a time in the future when this approach could be combined with checkpoint inhibitors for enhanced antitumor effects.

Dr, Weiner also noted that the T cells with receptors engineered to recognize MAGE-A3 are more specific for tumors, compared with approaches using chimeric antigen receptor T cells to treat certain hematologic malignancies. In that setting the chimeric antigen receptor T cells recognize and eliminate, for example, not only malignant B cells bearing a pan-B cell marker but also all normal B cells.

However, in the question and answer period, Dr. Lu said one problem with his approach is the possibility that not all cells in a tumor may express MAGE-A3.

There was no commercial funding of the study. Dr. Lu had no relevant financial disclosures. Dr. Weiner is an adviser, review panel member, or consultant, or has other relationships, with numerous pharmaceutical companies.

CD4+ T cells genetically engineered to recognize MAGE-A3, a protein found on many types of tumor cells but not on normal cells, were safely given to patients with metastatic cancers, and some of the patients had clinical responses.

Whereas the majority of current adoptive T-cell therapies have used genetically modified unpurified T cells or CD8+ (cytotoxic) T cells, Yong-Chen William Lu, Ph.D., of the surgery branch of the National Cancer Institute conducted a phase I trial of CD4+ (helper) T cells to evaluate their contribution to tumor killing. Preclinical and clinical studies indicated that CD4+ T cells can induce tumor regression.

Dr. Lu explained the individualized process of making the T cells for infusion, during a news conference at the annual meeting of the American Association for Cancer Research. First, T cells are harvested from the peripheral blood of a patient, from which CD4+ T cells are isolated. Using a retroviral vector, scientists insert the gene for a T-cell receptor that recognizes MAGE-A3 in conjunction with the HLA molecule DPB1*0401. In this way, the cells can recognize the tumor antigen in anyone of that HLA type. Then the cells carrying the engineered T-cell receptor are expanded in vitro and infused into the patient.

DPB1*0401 was chosen as the HLA genotype because “it is present in 60% of the Caucasian population. It is the highest one,” Dr. Lu said. MAGE-A3 is expressed on cells during fetal development and is later lost on normal tissues. But several tumor types, including some melanomas and some urothelial, esophageal, and cervical cancers reexpress this protein, making it a good target for immunotherapy.

The trial included patients of the HLA DPB1*0401 type with metastatic cancer that is MAGE-A3 positive. Patients had received at least one first-line treatment for metastatic disease and had been nonresponders or had had a recurrence of the tumor.

This phase I trial involved 14 patients in nine different dose cohorts, receiving from 10 million engineered T cells at the lowest dose to 78-103 billion cells in the highest cohort. Three patients in the middle and highest dosing cohorts achieved partial responses, one each with cervical, esophageal, and urothelial tumors. The partial response lasted 4 months for the patient with esophageal cancer and is ongoing at 7 months for the urothelial and 15 months for the cervical cancer patients.

In response to a question from the audience about adverse effects, Dr. Lu said patients had short-term elevations of circulating cytokines, “which only lasted for a few days,” and a fever lasting 1-2 weeks.

In summary, he said, “We think this first [CD4+] engineered T-cells therapy targeting MAGE-A3 is safe and has shown early clinical response.” Phase II trials are now beginning.

The approach of this immunotherapy method is different from that involved in using checkpoint inhibitors, “which essentially release the brakes of the immune system so the T cells can do their job of attacking the cancer,” commented Dr. Louis Weiner, director of the Georgetown Lombardi Cancer Center in Washington, D.C. “This is actually not trying to release brakes but essentially press on the accelerator, if you will, by using an expanded tumor-specific population of T cells that will then be able to hone in and attack the cancer.” He envisioned a time in the future when this approach could be combined with checkpoint inhibitors for enhanced antitumor effects.

Dr, Weiner also noted that the T cells with receptors engineered to recognize MAGE-A3 are more specific for tumors, compared with approaches using chimeric antigen receptor T cells to treat certain hematologic malignancies. In that setting the chimeric antigen receptor T cells recognize and eliminate, for example, not only malignant B cells bearing a pan-B cell marker but also all normal B cells.

However, in the question and answer period, Dr. Lu said one problem with his approach is the possibility that not all cells in a tumor may express MAGE-A3.

There was no commercial funding of the study. Dr. Lu had no relevant financial disclosures. Dr. Weiner is an adviser, review panel member, or consultant, or has other relationships, with numerous pharmaceutical companies.

CD4+ T cells genetically engineered to recognize MAGE-A3, a protein found on many types of tumor cells but not on normal cells, were safely given to patients with metastatic cancers, and some of the patients had clinical responses.

Whereas the majority of current adoptive T-cell therapies have used genetically modified unpurified T cells or CD8+ (cytotoxic) T cells, Yong-Chen William Lu, Ph.D., of the surgery branch of the National Cancer Institute conducted a phase I trial of CD4+ (helper) T cells to evaluate their contribution to tumor killing. Preclinical and clinical studies indicated that CD4+ T cells can induce tumor regression.

Dr. Lu explained the individualized process of making the T cells for infusion, during a news conference at the annual meeting of the American Association for Cancer Research. First, T cells are harvested from the peripheral blood of a patient, from which CD4+ T cells are isolated. Using a retroviral vector, scientists insert the gene for a T-cell receptor that recognizes MAGE-A3 in conjunction with the HLA molecule DPB1*0401. In this way, the cells can recognize the tumor antigen in anyone of that HLA type. Then the cells carrying the engineered T-cell receptor are expanded in vitro and infused into the patient.

DPB1*0401 was chosen as the HLA genotype because “it is present in 60% of the Caucasian population. It is the highest one,” Dr. Lu said. MAGE-A3 is expressed on cells during fetal development and is later lost on normal tissues. But several tumor types, including some melanomas and some urothelial, esophageal, and cervical cancers reexpress this protein, making it a good target for immunotherapy.

The trial included patients of the HLA DPB1*0401 type with metastatic cancer that is MAGE-A3 positive. Patients had received at least one first-line treatment for metastatic disease and had been nonresponders or had had a recurrence of the tumor.

This phase I trial involved 14 patients in nine different dose cohorts, receiving from 10 million engineered T cells at the lowest dose to 78-103 billion cells in the highest cohort. Three patients in the middle and highest dosing cohorts achieved partial responses, one each with cervical, esophageal, and urothelial tumors. The partial response lasted 4 months for the patient with esophageal cancer and is ongoing at 7 months for the urothelial and 15 months for the cervical cancer patients.

In response to a question from the audience about adverse effects, Dr. Lu said patients had short-term elevations of circulating cytokines, “which only lasted for a few days,” and a fever lasting 1-2 weeks.

In summary, he said, “We think this first [CD4+] engineered T-cells therapy targeting MAGE-A3 is safe and has shown early clinical response.” Phase II trials are now beginning.

The approach of this immunotherapy method is different from that involved in using checkpoint inhibitors, “which essentially release the brakes of the immune system so the T cells can do their job of attacking the cancer,” commented Dr. Louis Weiner, director of the Georgetown Lombardi Cancer Center in Washington, D.C. “This is actually not trying to release brakes but essentially press on the accelerator, if you will, by using an expanded tumor-specific population of T cells that will then be able to hone in and attack the cancer.” He envisioned a time in the future when this approach could be combined with checkpoint inhibitors for enhanced antitumor effects.

Dr, Weiner also noted that the T cells with receptors engineered to recognize MAGE-A3 are more specific for tumors, compared with approaches using chimeric antigen receptor T cells to treat certain hematologic malignancies. In that setting the chimeric antigen receptor T cells recognize and eliminate, for example, not only malignant B cells bearing a pan-B cell marker but also all normal B cells.

However, in the question and answer period, Dr. Lu said one problem with his approach is the possibility that not all cells in a tumor may express MAGE-A3.

There was no commercial funding of the study. Dr. Lu had no relevant financial disclosures. Dr. Weiner is an adviser, review panel member, or consultant, or has other relationships, with numerous pharmaceutical companies.

One-third of a group of heavily pretreated patients with advanced melanoma who received nivolumab monotherapy were alive 5 years after starting the drug, a phase I trial showed. Survival plateaued at 34% by 48 months, after which time disease control was maintained.

“What it does demonstrate is the importance of the durability of clinical benefit to patients [who] now we’re measuring in terms of years, as well as the memory aspect of how the immunologic memory can translate into benefit,” said Dr. Stephen Hodi, director of the melanoma center at Dana-Farber Cancer Institute in Boston during a news conference at the annual meeting of the American Association for Cancer Research.

© ASCO/Scott Morgan

Nivolumab is an immune checkpoint inhibitor that blocks PD-1, allowing enhanced antitumor immune responses. It is approved as a first-line agent for advanced melanoma, alone or in combination with ipilimumab. The approved dose for monotherapy is 3 mg/kg every 2 weeks.

The study randomized 107 patients (median age, 61 years; 67% male) to one of five doses ranging from 0.1 mg/kg to 10 mg/kg IV given every 2 weeks for up to 96 weeks. The patients had advanced melanoma at any site and had been on one to five lines of systemic therapy prior to entering the trial but could not have received any immune checkpoint inhibitors. They had treated and stable brain metastases and an ECOG (Eastern Cooperative Oncology Group) performance status of 0, 1, or 2. The minimum follow-up was 45 months.

Among all the patients, the median overall survival was 17.3 months (95% confidence interval, 12.5-37.8 months), and for those patients receiving 3-mg/kg doses, the median survival was 20.3 months (95% CI, 7.2 months and no upper confidence level reached). The Kaplan-Meier survival curves for all patients and those receiving the 3-mg/kg dose began to level off at about 36 months, and were essentially flat at 34% for all patients as a group from 48 months out to 5 years.

Five patients who achieved disease control but later had progressive disease were retreated with their original doses of nivolumab after being off the drug for more than 100 days. “In all five patients, disease control was obtained again, and this disease control was again durable,” Dr. Hodi reported.

Nivolumab monotherapy was safe and well tolerated. No study deaths or new safety signals were observed. The most common drug-related adverse effects were any grade of fatigue (29.9% of all patients; 47.1% of patients at the 3-mg/kg dose) and any grade of rash (23.4% and 11.8%, respectively). Although there were some grade 3-4 adverse events, adverse reactions led to study discontinuation for only 10.3% of the total patient group and 5.9% of patients on the 3-mg/kg dose.

Calling the study findings “very compelling,” conference moderator Dr. Louis Weiner, director of the Georgetown Lombardi Comprehensive Cancer Center in Washington, D.C., identified what he said is a key point of the study – the length of benefit. “What distinguishes immunotherapy at this point when it’s effective from other forms of cancer treatment is the durability of the benefit,” he said. “People who have good responses really seem to be protected against the disease returning in many cases.”

He asked Dr. Hodi if he would expect even better disease control results if nivolumab were combined with a different checkpoint inhibitor, such as ipilimumab. Dr. Hodi replied that it is reasonable to think that agents working through different mechanisms of action should produce even better results.

A reporter in the audience asked if it was Dr. Hodi’s practice to test tumors for PD-1 expression before using nivolumab. He replied that he and his colleagues do not routinely test for PD-1 because there have been observations that some tumors that test negative for the biomarker do respond to the drug.

One-third of a group of heavily pretreated patients with advanced melanoma who received nivolumab monotherapy were alive 5 years after starting the drug, a phase I trial showed. Survival plateaued at 34% by 48 months, after which time disease control was maintained.

“What it does demonstrate is the importance of the durability of clinical benefit to patients [who] now we’re measuring in terms of years, as well as the memory aspect of how the immunologic memory can translate into benefit,” said Dr. Stephen Hodi, director of the melanoma center at Dana-Farber Cancer Institute in Boston during a news conference at the annual meeting of the American Association for Cancer Research.

© ASCO/Scott Morgan

Nivolumab is an immune checkpoint inhibitor that blocks PD-1, allowing enhanced antitumor immune responses. It is approved as a first-line agent for advanced melanoma, alone or in combination with ipilimumab. The approved dose for monotherapy is 3 mg/kg every 2 weeks.

The study randomized 107 patients (median age, 61 years; 67% male) to one of five doses ranging from 0.1 mg/kg to 10 mg/kg IV given every 2 weeks for up to 96 weeks. The patients had advanced melanoma at any site and had been on one to five lines of systemic therapy prior to entering the trial but could not have received any immune checkpoint inhibitors. They had treated and stable brain metastases and an ECOG (Eastern Cooperative Oncology Group) performance status of 0, 1, or 2. The minimum follow-up was 45 months.

Among all the patients, the median overall survival was 17.3 months (95% confidence interval, 12.5-37.8 months), and for those patients receiving 3-mg/kg doses, the median survival was 20.3 months (95% CI, 7.2 months and no upper confidence level reached). The Kaplan-Meier survival curves for all patients and those receiving the 3-mg/kg dose began to level off at about 36 months, and were essentially flat at 34% for all patients as a group from 48 months out to 5 years.

Five patients who achieved disease control but later had progressive disease were retreated with their original doses of nivolumab after being off the drug for more than 100 days. “In all five patients, disease control was obtained again, and this disease control was again durable,” Dr. Hodi reported.

Nivolumab monotherapy was safe and well tolerated. No study deaths or new safety signals were observed. The most common drug-related adverse effects were any grade of fatigue (29.9% of all patients; 47.1% of patients at the 3-mg/kg dose) and any grade of rash (23.4% and 11.8%, respectively). Although there were some grade 3-4 adverse events, adverse reactions led to study discontinuation for only 10.3% of the total patient group and 5.9% of patients on the 3-mg/kg dose.

Calling the study findings “very compelling,” conference moderator Dr. Louis Weiner, director of the Georgetown Lombardi Comprehensive Cancer Center in Washington, D.C., identified what he said is a key point of the study – the length of benefit. “What distinguishes immunotherapy at this point when it’s effective from other forms of cancer treatment is the durability of the benefit,” he said. “People who have good responses really seem to be protected against the disease returning in many cases.”

He asked Dr. Hodi if he would expect even better disease control results if nivolumab were combined with a different checkpoint inhibitor, such as ipilimumab. Dr. Hodi replied that it is reasonable to think that agents working through different mechanisms of action should produce even better results.

A reporter in the audience asked if it was Dr. Hodi’s practice to test tumors for PD-1 expression before using nivolumab. He replied that he and his colleagues do not routinely test for PD-1 because there have been observations that some tumors that test negative for the biomarker do respond to the drug.

One-third of a group of heavily pretreated patients with advanced melanoma who received nivolumab monotherapy were alive 5 years after starting the drug, a phase I trial showed. Survival plateaued at 34% by 48 months, after which time disease control was maintained.

“What it does demonstrate is the importance of the durability of clinical benefit to patients [who] now we’re measuring in terms of years, as well as the memory aspect of how the immunologic memory can translate into benefit,” said Dr. Stephen Hodi, director of the melanoma center at Dana-Farber Cancer Institute in Boston during a news conference at the annual meeting of the American Association for Cancer Research.

© ASCO/Scott Morgan

Nivolumab is an immune checkpoint inhibitor that blocks PD-1, allowing enhanced antitumor immune responses. It is approved as a first-line agent for advanced melanoma, alone or in combination with ipilimumab. The approved dose for monotherapy is 3 mg/kg every 2 weeks.

The study randomized 107 patients (median age, 61 years; 67% male) to one of five doses ranging from 0.1 mg/kg to 10 mg/kg IV given every 2 weeks for up to 96 weeks. The patients had advanced melanoma at any site and had been on one to five lines of systemic therapy prior to entering the trial but could not have received any immune checkpoint inhibitors. They had treated and stable brain metastases and an ECOG (Eastern Cooperative Oncology Group) performance status of 0, 1, or 2. The minimum follow-up was 45 months.

Among all the patients, the median overall survival was 17.3 months (95% confidence interval, 12.5-37.8 months), and for those patients receiving 3-mg/kg doses, the median survival was 20.3 months (95% CI, 7.2 months and no upper confidence level reached). The Kaplan-Meier survival curves for all patients and those receiving the 3-mg/kg dose began to level off at about 36 months, and were essentially flat at 34% for all patients as a group from 48 months out to 5 years.

Five patients who achieved disease control but later had progressive disease were retreated with their original doses of nivolumab after being off the drug for more than 100 days. “In all five patients, disease control was obtained again, and this disease control was again durable,” Dr. Hodi reported.

Nivolumab monotherapy was safe and well tolerated. No study deaths or new safety signals were observed. The most common drug-related adverse effects were any grade of fatigue (29.9% of all patients; 47.1% of patients at the 3-mg/kg dose) and any grade of rash (23.4% and 11.8%, respectively). Although there were some grade 3-4 adverse events, adverse reactions led to study discontinuation for only 10.3% of the total patient group and 5.9% of patients on the 3-mg/kg dose.

Calling the study findings “very compelling,” conference moderator Dr. Louis Weiner, director of the Georgetown Lombardi Comprehensive Cancer Center in Washington, D.C., identified what he said is a key point of the study – the length of benefit. “What distinguishes immunotherapy at this point when it’s effective from other forms of cancer treatment is the durability of the benefit,” he said. “People who have good responses really seem to be protected against the disease returning in many cases.”

He asked Dr. Hodi if he would expect even better disease control results if nivolumab were combined with a different checkpoint inhibitor, such as ipilimumab. Dr. Hodi replied that it is reasonable to think that agents working through different mechanisms of action should produce even better results.

A reporter in the audience asked if it was Dr. Hodi’s practice to test tumors for PD-1 expression before using nivolumab. He replied that he and his colleagues do not routinely test for PD-1 because there have been observations that some tumors that test negative for the biomarker do respond to the drug.