CAR T-cells induce remissions, avoid GVHD in relapsed B-cell malignancies

In patients with B-cell malignancies who did not obtain remissions after allogeneic hematopoietic stem-cell transplantation (alloHSCT), infusion of anti-CD19 chimeric antigen receptor (CAR19) T-cells induced remissions without causing graft-versus-host disease (GVHD).

Of 20 patients treated, 6 obtained complete remission and 2 obtained partial remissions, while none of the patients experienced new-onset acute GVHD.

“The increased antimalignancy potency of CAR19 T-cells allowed small doses of T-cells to eradicate malignancy without causing GVHD; therefore, this work demonstrates a solution to the central problem of alloHSCT, the separation of [graft-versus-malignancy] from GVHD,” wrote Dr. Jennifer Brudno of the National Cancer Institute, Bethesda, Md., and colleagues (J Clin Onc. 2016 Jan. 25. doi: 10.1200/JCO.2015.64.5929).

In general, CAR19 T-cells did not persist longer than 4 weeks, the median time it takes for GVHD to develop after donor lymphocyte infusion, which may be a factor in avoiding GVHD. Smaller doses may be another contributing factor: CAR19 T-cell doses administered in the trial ranged from 106/kg to 107/kg, which is 10-fold smaller than typical donor lymphocyte infusions.

In contrast to previous CAR T-cell studies, patients did not receive chemotherapy before CAR19 T-cell infusion, so endogenous T-cells and natural killer cells were not depleted. Evidence indicates that lymphocyte depletion enhances antitumor activity of adoptively transferred T-cells, but the current results indicate that prior lymphocyte depletion is not an absolute requirement.

The CAR19 T-cell infusion was especially effective in acute lymphoblastic leukemia (ALL), with four of the five ALL patients obtaining complete remission. Patients with chronic lymphocyte leukemia and lymphoma also obtained remissions.

Toxicities observed were consistent with previous CAR T-cell studies and included fever, tachycardia, and hypotension, indicative of cytokine release syndrome.

Peak levels of CAR19 T-cells were significantly higher in patients with complete or partial responses, and patients who did not obtain a complete or partial response were more likely to have undetectable or very low levels. Increasing peak blood levels of CAR19 T-cells in vivo is an important goal for future research, according to investigators. Since endogenous CD19+ cells may promote proliferation of CAR19 T- cells, CD19+ cellular vaccines might enhance CAR19 T-cell proliferation in patients with low levels, they suggested.

Administration of programmed cell death protein-1 (PD-1) antagonists may also offer improvements. High levels of PD-1 expression on CAR19 T-cells were observed at the time of peak blood CAR19 T-cell levels.

Dr. Brudno reported having no disclosures. Dr. Goy and Dr. Rosenberg reported ties to industry, and Dr. Kochenderfer reported patents pending on CAR T-cell therapy.

In patients with B-cell malignancies who did not obtain remissions after allogeneic hematopoietic stem-cell transplantation (alloHSCT), infusion of anti-CD19 chimeric antigen receptor (CAR19) T-cells induced remissions without causing graft-versus-host disease (GVHD).

Of 20 patients treated, 6 obtained complete remission and 2 obtained partial remissions, while none of the patients experienced new-onset acute GVHD.

“The increased antimalignancy potency of CAR19 T-cells allowed small doses of T-cells to eradicate malignancy without causing GVHD; therefore, this work demonstrates a solution to the central problem of alloHSCT, the separation of [graft-versus-malignancy] from GVHD,” wrote Dr. Jennifer Brudno of the National Cancer Institute, Bethesda, Md., and colleagues (J Clin Onc. 2016 Jan. 25. doi: 10.1200/JCO.2015.64.5929).

In general, CAR19 T-cells did not persist longer than 4 weeks, the median time it takes for GVHD to develop after donor lymphocyte infusion, which may be a factor in avoiding GVHD. Smaller doses may be another contributing factor: CAR19 T-cell doses administered in the trial ranged from 106/kg to 107/kg, which is 10-fold smaller than typical donor lymphocyte infusions.

In contrast to previous CAR T-cell studies, patients did not receive chemotherapy before CAR19 T-cell infusion, so endogenous T-cells and natural killer cells were not depleted. Evidence indicates that lymphocyte depletion enhances antitumor activity of adoptively transferred T-cells, but the current results indicate that prior lymphocyte depletion is not an absolute requirement.

The CAR19 T-cell infusion was especially effective in acute lymphoblastic leukemia (ALL), with four of the five ALL patients obtaining complete remission. Patients with chronic lymphocyte leukemia and lymphoma also obtained remissions.

Toxicities observed were consistent with previous CAR T-cell studies and included fever, tachycardia, and hypotension, indicative of cytokine release syndrome.

Peak levels of CAR19 T-cells were significantly higher in patients with complete or partial responses, and patients who did not obtain a complete or partial response were more likely to have undetectable or very low levels. Increasing peak blood levels of CAR19 T-cells in vivo is an important goal for future research, according to investigators. Since endogenous CD19+ cells may promote proliferation of CAR19 T- cells, CD19+ cellular vaccines might enhance CAR19 T-cell proliferation in patients with low levels, they suggested.

Administration of programmed cell death protein-1 (PD-1) antagonists may also offer improvements. High levels of PD-1 expression on CAR19 T-cells were observed at the time of peak blood CAR19 T-cell levels.

Dr. Brudno reported having no disclosures. Dr. Goy and Dr. Rosenberg reported ties to industry, and Dr. Kochenderfer reported patents pending on CAR T-cell therapy.

In patients with B-cell malignancies who did not obtain remissions after allogeneic hematopoietic stem-cell transplantation (alloHSCT), infusion of anti-CD19 chimeric antigen receptor (CAR19) T-cells induced remissions without causing graft-versus-host disease (GVHD).

Of 20 patients treated, 6 obtained complete remission and 2 obtained partial remissions, while none of the patients experienced new-onset acute GVHD.

“The increased antimalignancy potency of CAR19 T-cells allowed small doses of T-cells to eradicate malignancy without causing GVHD; therefore, this work demonstrates a solution to the central problem of alloHSCT, the separation of [graft-versus-malignancy] from GVHD,” wrote Dr. Jennifer Brudno of the National Cancer Institute, Bethesda, Md., and colleagues (J Clin Onc. 2016 Jan. 25. doi: 10.1200/JCO.2015.64.5929).

In general, CAR19 T-cells did not persist longer than 4 weeks, the median time it takes for GVHD to develop after donor lymphocyte infusion, which may be a factor in avoiding GVHD. Smaller doses may be another contributing factor: CAR19 T-cell doses administered in the trial ranged from 106/kg to 107/kg, which is 10-fold smaller than typical donor lymphocyte infusions.

In contrast to previous CAR T-cell studies, patients did not receive chemotherapy before CAR19 T-cell infusion, so endogenous T-cells and natural killer cells were not depleted. Evidence indicates that lymphocyte depletion enhances antitumor activity of adoptively transferred T-cells, but the current results indicate that prior lymphocyte depletion is not an absolute requirement.

The CAR19 T-cell infusion was especially effective in acute lymphoblastic leukemia (ALL), with four of the five ALL patients obtaining complete remission. Patients with chronic lymphocyte leukemia and lymphoma also obtained remissions.

Toxicities observed were consistent with previous CAR T-cell studies and included fever, tachycardia, and hypotension, indicative of cytokine release syndrome.

Peak levels of CAR19 T-cells were significantly higher in patients with complete or partial responses, and patients who did not obtain a complete or partial response were more likely to have undetectable or very low levels. Increasing peak blood levels of CAR19 T-cells in vivo is an important goal for future research, according to investigators. Since endogenous CD19+ cells may promote proliferation of CAR19 T- cells, CD19+ cellular vaccines might enhance CAR19 T-cell proliferation in patients with low levels, they suggested.

Administration of programmed cell death protein-1 (PD-1) antagonists may also offer improvements. High levels of PD-1 expression on CAR19 T-cells were observed at the time of peak blood CAR19 T-cell levels.

Dr. Brudno reported having no disclosures. Dr. Goy and Dr. Rosenberg reported ties to industry, and Dr. Kochenderfer reported patents pending on CAR T-cell therapy.