Meeting News

B-cell maturation antigen-targeted CAR T-cell therapy potent in advanced myeloma

Damian J. Green, MD
Damian J. Green

SAN DIEGO — B-cell maturation antigen chimeric antigen receptor T cells that harbor a fully human single-chain variable fragment with a defined composition of CD4-positive and CD8-positive T cells appeared potent among patients with heavily pretreated, high-risk multiple myeloma, according to study results presented at ASH Annual Meeting and Exposition.

Researchers observed responses with total cell doses as low as 5 x 107 cells/kg. The approach also appeared well tolerated, with no grade 3 or higher cytokine release syndrome and no dose-limiting toxicities.

“In oncology, we usually think about dose in relation to traditional agents. In this case, we are talking about cells that expand in vivo and have different phenotypes and different features that may be every bit as important — if not more important — than the absolute number of cells you put in,” Damian J. Green, MD, hematologist/oncologist at Seattle Cancer Care Alliance, associate member at Fred Hutchinson Cancer Research Center and associate professor of medical oncology at University of Washington School of Medicine, told HemOnc Today.

“I don’t want to overplay the dose issue, but if you can get robust responses and not see those kinds of toxicities, then you’re hitting a sweet spot. Maybe we can do that.”

Despite the recent development of effective therapies for myeloma, nearly all patients relapse. High-risk features are associated with short median survival.

Use of CAR T cells that target B-cell maturation antigen (BCMA) has demonstrated potential for treatment of multiple myeloma; however, response durability has not been established.

In their phase 1, first-in-human dose-escalation study, Green — a HemOnc Today Next Gen Innovator — and colleagues aimed to infuse genetically modified T cells with uniform composition of CD8-positive and CD4-positive cells to facilitate the evaluation of each subset’s function.

“There are differences in CAR T-cell product composition that may have a big impact. We have tried to mitigate that impact by generating CD4 and CD8 CAR T cells separately,” Green said. “That takes more work but, scientifically, it makes sense to give patients something we understand well so we can study the downstream impact. The more defined a product is when you put it into a patient, the more that facilitates understanding of what you see later on.”

The analysis included patients with relapsed or refractory multiple myeloma who had at least 10% CD138-positive bone marrow plasma cells and at least 5% BCMA expression by flow cytometry.

Researchers stratified patients into two cohorts based on bone marrow involvement (Cohort A, 10% to 30%; Cohort B, > 30%) to help determine the effect of disease burden on outcome.

CD8-postive and CD4-positive T cells — which had been isolated via positive selection, enriched separately by immunomagnetic selection and then cryopreserved — were stimulated in independent cultures with anti-CD3 and anti-CD28 paramagnetic beads.

Cells then were transduced with a third-generation lentiviral vector that encoded a fully human BCMA single-chain variable fragment, as well as 4-1BB and CD3 zeta signaling domains.

Following in vitro expansion, investigators formulated the cell product for infusion in a 1:1 ratio of CD4-positive and CD8-positive BCMA CAR T cells.

Eleven patients (median, 57 years; range, 43-76) who had undergone a median 11 prior treatments (range, 8-20) underwent treatment.

All patients had at least one high-risk cytogenetic feature. These included 17p deletion (n = 5), t(4;14) translocation (n = 2), t(14;16) translocation (n = 1) and +1q/1p- (n=9). The majority had two or more high-risk cytogenetic features (54%) and underwent prior autologous stem cell transplant (82%). Slightly less than half (45%) underwent prior allogeneic transplant and one (9%) had plasma cell leukemia. One patient had undergone prior CAR T-cell infusion.

At enrollment, median involved free light chain was 63.5 mg/dL (range, 6.89-502.96; n=9) and median monoclonal protein was 1.9 g/dL (range, 0.5-6.5; n=9).

Patients underwent lymphodepleting chemotherapy, followed by CAR T-cell infusion at a starting dose of 5 x 107 cells/kg. The dose for four patients was increased to 15 x 107 cells/kg.

By day 28, all 11 evaluable patients had achieved response and had no detectable abnormal bone marrow plasma cells by immunohistochemistry and high-sensitivity flow cytometry.

BCMA CAR T cells remained detectable up to 180 days after infusion, representing up to 32% of CD4-positive lymphocytes and 3.1% of CD8-positive lymphocytes.

Two patients who received the lowest CAR T cell dose have relapsed.

A tumor biopsy from one of these patients demonstrated the presence of a BCMA-negative plasma cell population, a 70% decline in fraction of myeloma cells that expressed BCMA by flow cytometry, and a fivefold reduction in BCMA antigen-binding capacity on myeloma cells that retained target expression. Researchers did not observe a cytotoxic T lymphocyte response to the trans-gene product in this patient.

The treatment approach appeared well tolerated.

One patient experienced elevated liver transaminase levels that resolved after 1 day. No other non-hematologic toxicities were >grade 3 by the Common Terminology Criteria for Adverse Events (CTCAE).

No dose-limiting toxicity occurred during the 28-day monitoring window. All cases of cytokine release syndrome were grade 2 or lower, and investigators observed neurological toxicity in one patient which was responsive to tocilizumab and dexamethasone.

“We should remember that we are at the lower dose levels. This is promising, but it is a dose-escalation study so we’ll see what happens going forward,” Green said.

Dose escalation on this trial is ongoing. Next-generation sequencing and multiparameter high-sensitivity flow cytometry studies to assess for minimal residual disease also are underway.

“We are very encouraged by what we have seen in terms of response,” Green told HemOnc Today. “Now we need to really drill down and understand, if patients escape and relapse, why are they relapsing? And if they respond and do well, why? We are trying to take a very measured approach to that. Our study involves sequential bone marrow biopsies. We are using a variety of different tools to investigate those methods of relapse, including looking at RNA sequencing to evaluate not just the tumor cells but all surrounding cells in the bone marrow microenvironment to see what kind of interplay is going on and determine what factors might support response or contribute to resistance.”

Despite the early results, Green emphasized the need to remain cautious.

“I don’t want to overstate the findings because sometimes patients will say, ‘I want this before stem cell transplant,’ and I don’t think that’s the right approach,” he told HemOnc Today. “There are approaches that we have that are well validated ... in most cases patients should first go that route and take the therapies with which we have a long experience.” – by Mark Leiser

Reference:

Green DJ, et al. Abstract 1011. Presented at: ASH Annual Meeting and Exposition; Dec. 1-4, 2018; San Diego.

Disclosures: Green reports research funding and patents/royalties from Juno Therapeutics. Please see the abstract for all other authors’ relevant financial disclosures.

Damian J. Green, MD
Damian J. Green

SAN DIEGO — B-cell maturation antigen chimeric antigen receptor T cells that harbor a fully human single-chain variable fragment with a defined composition of CD4-positive and CD8-positive T cells appeared potent among patients with heavily pretreated, high-risk multiple myeloma, according to study results presented at ASH Annual Meeting and Exposition.

Researchers observed responses with total cell doses as low as 5 x 107 cells/kg. The approach also appeared well tolerated, with no grade 3 or higher cytokine release syndrome and no dose-limiting toxicities.

“In oncology, we usually think about dose in relation to traditional agents. In this case, we are talking about cells that expand in vivo and have different phenotypes and different features that may be every bit as important — if not more important — than the absolute number of cells you put in,” Damian J. Green, MD, hematologist/oncologist at Seattle Cancer Care Alliance, associate member at Fred Hutchinson Cancer Research Center and associate professor of medical oncology at University of Washington School of Medicine, told HemOnc Today.

“I don’t want to overplay the dose issue, but if you can get robust responses and not see those kinds of toxicities, then you’re hitting a sweet spot. Maybe we can do that.”

Despite the recent development of effective therapies for myeloma, nearly all patients relapse. High-risk features are associated with short median survival.

Use of CAR T cells that target B-cell maturation antigen (BCMA) has demonstrated potential for treatment of multiple myeloma; however, response durability has not been established.

In their phase 1, first-in-human dose-escalation study, Green — a HemOnc Today Next Gen Innovator — and colleagues aimed to infuse genetically modified T cells with uniform composition of CD8-positive and CD4-positive cells to facilitate the evaluation of each subset’s function.

“There are differences in CAR T-cell product composition that may have a big impact. We have tried to mitigate that impact by generating CD4 and CD8 CAR T cells separately,” Green said. “That takes more work but, scientifically, it makes sense to give patients something we understand well so we can study the downstream impact. The more defined a product is when you put it into a patient, the more that facilitates understanding of what you see later on.”

The analysis included patients with relapsed or refractory multiple myeloma who had at least 10% CD138-positive bone marrow plasma cells and at least 5% BCMA expression by flow cytometry.

Researchers stratified patients into two cohorts based on bone marrow involvement (Cohort A, 10% to 30%; Cohort B, > 30%) to help determine the effect of disease burden on outcome.

PAGE BREAK

CD8-postive and CD4-positive T cells — which had been isolated via positive selection, enriched separately by immunomagnetic selection and then cryopreserved — were stimulated in independent cultures with anti-CD3 and anti-CD28 paramagnetic beads.

Cells then were transduced with a third-generation lentiviral vector that encoded a fully human BCMA single-chain variable fragment, as well as 4-1BB and CD3 zeta signaling domains.

Following in vitro expansion, investigators formulated the cell product for infusion in a 1:1 ratio of CD4-positive and CD8-positive BCMA CAR T cells.

Eleven patients (median, 57 years; range, 43-76) who had undergone a median 11 prior treatments (range, 8-20) underwent treatment.

All patients had at least one high-risk cytogenetic feature. These included 17p deletion (n = 5), t(4;14) translocation (n = 2), t(14;16) translocation (n = 1) and +1q/1p- (n=9). The majority had two or more high-risk cytogenetic features (54%) and underwent prior autologous stem cell transplant (82%). Slightly less than half (45%) underwent prior allogeneic transplant and one (9%) had plasma cell leukemia. One patient had undergone prior CAR T-cell infusion.

At enrollment, median involved free light chain was 63.5 mg/dL (range, 6.89-502.96; n=9) and median monoclonal protein was 1.9 g/dL (range, 0.5-6.5; n=9).

Patients underwent lymphodepleting chemotherapy, followed by CAR T-cell infusion at a starting dose of 5 x 107 cells/kg. The dose for four patients was increased to 15 x 107 cells/kg.

By day 28, all 11 evaluable patients had achieved response and had no detectable abnormal bone marrow plasma cells by immunohistochemistry and high-sensitivity flow cytometry.

BCMA CAR T cells remained detectable up to 180 days after infusion, representing up to 32% of CD4-positive lymphocytes and 3.1% of CD8-positive lymphocytes.

Two patients who received the lowest CAR T cell dose have relapsed.

A tumor biopsy from one of these patients demonstrated the presence of a BCMA-negative plasma cell population, a 70% decline in fraction of myeloma cells that expressed BCMA by flow cytometry, and a fivefold reduction in BCMA antigen-binding capacity on myeloma cells that retained target expression. Researchers did not observe a cytotoxic T lymphocyte response to the trans-gene product in this patient.

The treatment approach appeared well tolerated.

One patient experienced elevated liver transaminase levels that resolved after 1 day. No other non-hematologic toxicities were >grade 3 by the Common Terminology Criteria for Adverse Events (CTCAE).

No dose-limiting toxicity occurred during the 28-day monitoring window. All cases of cytokine release syndrome were grade 2 or lower, and investigators observed neurological toxicity in one patient which was responsive to tocilizumab and dexamethasone.

PAGE BREAK

“We should remember that we are at the lower dose levels. This is promising, but it is a dose-escalation study so we’ll see what happens going forward,” Green said.

Dose escalation on this trial is ongoing. Next-generation sequencing and multiparameter high-sensitivity flow cytometry studies to assess for minimal residual disease also are underway.

“We are very encouraged by what we have seen in terms of response,” Green told HemOnc Today. “Now we need to really drill down and understand, if patients escape and relapse, why are they relapsing? And if they respond and do well, why? We are trying to take a very measured approach to that. Our study involves sequential bone marrow biopsies. We are using a variety of different tools to investigate those methods of relapse, including looking at RNA sequencing to evaluate not just the tumor cells but all surrounding cells in the bone marrow microenvironment to see what kind of interplay is going on and determine what factors might support response or contribute to resistance.”

Despite the early results, Green emphasized the need to remain cautious.

“I don’t want to overstate the findings because sometimes patients will say, ‘I want this before stem cell transplant,’ and I don’t think that’s the right approach,” he told HemOnc Today. “There are approaches that we have that are well validated ... in most cases patients should first go that route and take the therapies with which we have a long experience.” – by Mark Leiser

Reference:

Green DJ, et al. Abstract 1011. Presented at: ASH Annual Meeting and Exposition; Dec. 1-4, 2018; San Diego.

Disclosures: Green reports research funding and patents/royalties from Juno Therapeutics. Please see the abstract for all other authors’ relevant financial disclosures.

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