In the JournalsPerspective

CAR T-cell therapy shows activity in lymphoma despite lack of measurable disease

Michael R. Bishop, MD
Michael R. Bishop

Tisagenlecleucel showed measurable in vivo expansion in patients with relapsed or refractory diffuse large B-cell lymphoma who had no measurable disease after bridging therapy, according to a recent post-hoc exploratory analysis of a JULIET trial subset published in Blood Advances.

Post-infusion expansion of tisagenlecleucel (Kymriah; Novartis) was observed in all seven patients who had no measurable disease after bridging chemotherapy, with five of seven patients remaining progression free more than 12 months after infusion.

Data from the seven patients in this subset were withheld from the overall efficacy analysis published by the FDA for its approval of tisagenlecleucel for DLBCL, according to Michael R. Bishop, MD, the study’s lead author and a professor of medicine and director of the Hematopoietic Stem Cell Transplantation Program at the University of Chicago.

“These patients were excluded, and we thought they were interesting from both a biology and clinical standpoint,” he told Cell Therapy Next. “We wanted to know what happened to these patients and that’s what led to this analysis.”

Overall, 92% of the original JULIET study population (n = 111) received bridging therapy after study entry and before pre-infusion lymphodepletion. A subset of seven of the patients (5 women, 2 men; age range 54-71 years) had a complete response to bridging therapy and no measurable disease.

All seven patients who had a complete response to bridging therapy showed rapid expansion of tisagenlecleucel during the first 28 days after infusion, and CAR transgene levels were measurable up to 2 years after the infusion. Mean transgene levels at peak expansion in the subset were comparable with overall values for all JULIET trial participants. All seven patients maintained a complete response at 3-month follow-up, and five of seven patients were progression free at more than 12-month follow-up.

“Expansion was close to what we see with normal patients, but on the lower end of expansion,” Bishop told Cell Therapy Next. “This may be a reason why [cytokine release syndrome (CRS)] was lower and not necessarily because of lower disease burden. Then again, the expansion may correlate with low disease burden as well, so the two may go hand in hand.”

CRS occurred in four of seven patients in the subset, with two patients experiencing grade 2 or 3 CRS according to the Penn grading scale; one patient had grade 1 neurotoxicity. None of the patients required additional therapy to manage CRS.

When asked if the low rate of CRS in this subset was the result of a lack of measurable disease, Bishop responded “that’s one hypothesis,” adding, “there is a known correlation with CRS and higher disease burden; considering that these patients had little to no disease burden, that is a strong possibility.”

One of the key takeaways from this analysis, according to Bishop, is that CAR T cells will expand in patients without measurable disease at the time of infusion.

“The second is that this group of patients, on a relative basis, did possibly obtain benefit from CAR T cells, although the numbers are too small to make any firm conclusions,” he said. “However, the majority of the patients did appear to have long-term remission.”

Bishop said some researchers have expressed concerns about using CAR T-cell therapy in patients who are in complete remission and that the cells will not expand in this patient population. “We should think about using CAR T earlier and up front and we shouldn’t necessarily exclude patients in complete remission,” Bishop said, adding that his interest lies in doing further trials on this group of patients.

“The FDA indications don’t stipulate if a patient is in remission after the bridging chemotherapy whether or not you then give them the CAR T cells,” Bishop said. “For that group of patients, investigators may want to re-think whether or not they should go ahead and give CAR T cells to their patients.” – by Drew Amorosi

Reference:

Schuster SJ, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1804980.

For more information:

Michael R. Bishop, MD, can be reached at University of Chicago, 5841 S. Maryland Ave., Chicago, IL 60637; email: mbishop@medicine.bsd.uchicago.edu.

Disclosures: Bishop reports consultant/speaker’s bureau roles with Agios Pharmaceuticals, Celgene, CRISPR Therapeutics, Juno Therapeutics, Kite Pharma, Novartis and Optum; board of directors/advisory committee roles with Juno Therapeutics, Kite Pharma and Novartis; research funding from Juno Therapeutics, Kite Pharma and Novartis; honoraria from Agios Pharmaceuticals, Celgene, CRISPR Therapeutics, Juno Therapeutics, Kite Pharma, Novartis and Optum; and was employed by Optum. Please see the study for all other authors’ relevant financial disclosures.

Michael R. Bishop, MD
Michael R. Bishop

Tisagenlecleucel showed measurable in vivo expansion in patients with relapsed or refractory diffuse large B-cell lymphoma who had no measurable disease after bridging therapy, according to a recent post-hoc exploratory analysis of a JULIET trial subset published in Blood Advances.

Post-infusion expansion of tisagenlecleucel (Kymriah; Novartis) was observed in all seven patients who had no measurable disease after bridging chemotherapy, with five of seven patients remaining progression free more than 12 months after infusion.

Data from the seven patients in this subset were withheld from the overall efficacy analysis published by the FDA for its approval of tisagenlecleucel for DLBCL, according to Michael R. Bishop, MD, the study’s lead author and a professor of medicine and director of the Hematopoietic Stem Cell Transplantation Program at the University of Chicago.

“These patients were excluded, and we thought they were interesting from both a biology and clinical standpoint,” he told Cell Therapy Next. “We wanted to know what happened to these patients and that’s what led to this analysis.”

Overall, 92% of the original JULIET study population (n = 111) received bridging therapy after study entry and before pre-infusion lymphodepletion. A subset of seven of the patients (5 women, 2 men; age range 54-71 years) had a complete response to bridging therapy and no measurable disease.

All seven patients who had a complete response to bridging therapy showed rapid expansion of tisagenlecleucel during the first 28 days after infusion, and CAR transgene levels were measurable up to 2 years after the infusion. Mean transgene levels at peak expansion in the subset were comparable with overall values for all JULIET trial participants. All seven patients maintained a complete response at 3-month follow-up, and five of seven patients were progression free at more than 12-month follow-up.

“Expansion was close to what we see with normal patients, but on the lower end of expansion,” Bishop told Cell Therapy Next. “This may be a reason why [cytokine release syndrome (CRS)] was lower and not necessarily because of lower disease burden. Then again, the expansion may correlate with low disease burden as well, so the two may go hand in hand.”

CRS occurred in four of seven patients in the subset, with two patients experiencing grade 2 or 3 CRS according to the Penn grading scale; one patient had grade 1 neurotoxicity. None of the patients required additional therapy to manage CRS.

PAGE BREAK

When asked if the low rate of CRS in this subset was the result of a lack of measurable disease, Bishop responded “that’s one hypothesis,” adding, “there is a known correlation with CRS and higher disease burden; considering that these patients had little to no disease burden, that is a strong possibility.”

One of the key takeaways from this analysis, according to Bishop, is that CAR T cells will expand in patients without measurable disease at the time of infusion.

“The second is that this group of patients, on a relative basis, did possibly obtain benefit from CAR T cells, although the numbers are too small to make any firm conclusions,” he said. “However, the majority of the patients did appear to have long-term remission.”

Bishop said some researchers have expressed concerns about using CAR T-cell therapy in patients who are in complete remission and that the cells will not expand in this patient population. “We should think about using CAR T earlier and up front and we shouldn’t necessarily exclude patients in complete remission,” Bishop said, adding that his interest lies in doing further trials on this group of patients.

“The FDA indications don’t stipulate if a patient is in remission after the bridging chemotherapy whether or not you then give them the CAR T cells,” Bishop said. “For that group of patients, investigators may want to re-think whether or not they should go ahead and give CAR T cells to their patients.” – by Drew Amorosi

Reference:

Schuster SJ, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1804980.

For more information:

Michael R. Bishop, MD, can be reached at University of Chicago, 5841 S. Maryland Ave., Chicago, IL 60637; email: mbishop@medicine.bsd.uchicago.edu.

Disclosures: Bishop reports consultant/speaker’s bureau roles with Agios Pharmaceuticals, Celgene, CRISPR Therapeutics, Juno Therapeutics, Kite Pharma, Novartis and Optum; board of directors/advisory committee roles with Juno Therapeutics, Kite Pharma and Novartis; research funding from Juno Therapeutics, Kite Pharma and Novartis; honoraria from Agios Pharmaceuticals, Celgene, CRISPR Therapeutics, Juno Therapeutics, Kite Pharma, Novartis and Optum; and was employed by Optum. Please see the study for all other authors’ relevant financial disclosures.

    Perspective

     
    Tanya Siddiqi
    Stephen Forman 
    Stephen J. Forman

    Bishop and colleague report an intriguing observation from the JULIET trial. Seven patients with relapsed DLBCL who were in complete remission at the time of tisagenlecleucel infusion experienced expansion and persistence of CAR T cells. 

    These patients had failed several previous lines of therapy, and four had undergone previous autologous stem cell transplantation. Five of the seven patients are still in remission, with median follow-up of 14.5 months. Robust and durable expansion of tisagenlecleucel was observed among all seven patients who lacked an obvious lymphoma-related antigen drive.

    It is likely that the type of T cell transduced during CAR T-cell manufacturing and/or the costimulatory signal used in the CAR T-cell construct affect CAR T-cell expansion in vivo, in addition to the presence of tumor-related CD19 antigen expression. Other types of CAR T cells might not behave similarly in the setting of low/no antigen, as has been observed by Wang and colleagues.

    Further studies will need to investigate the relationship between CAR product cellular composition and antigen stimulation thresholds. Nevertheless, we believe these observations may pave the way for CAR T cells to be tested as consolidation therapy among patients with high-risk DLBCL as part of upfront therapy. 

    In this study, two of seven patients in complete remission eventually relapsed, and it would be interesting to know their tumor characteristics (eg, CD19 status, PD1/PD-L1 expression, etc.). The fact that tisagenlecleucel was still measurable among these patients at relapse suggests that, as in other patients with large cell lymphoma, novel treatment strategies will need to be developed for such patients. Finally, it was observed that these seven patients with undetectable disease at the time of treatment also experienced less CRS and neurotoxicity compared with the overall JULIET trial population, suggesting disease burden may play a role in the intensity of tisagenlecleucel-related side effects.

    Overall, we believe the observations in this report raise several important ideas for the CAR T-cell field that may contribute to testing the timing of CAR T-cell therapy to improve the cure rate for patients with lymphoma.

    Reference:
    Wang X, et al. Blood. 2016;doi:10.1182/blood-2015-12-686725.

    Tanya Siddiqi, MD
    Stephen J. Forman, MD
    City of Hope

    Disclosures: Siddiqi reports consultant/advisory or speakers bureau roles with or travel accommodations from AstraZeneca, BeiGene, Juno Therapeutics, Pharmacyclics/Janssen and Seattle Genetics and research funding to her institution from Acerta Pharma, BeiGene, Celgene, Juno Therapeutics, Kite Pharma, Oncternal Therapeutics, PCYC and TG Therapeutics. Forman reports lab support from and a consultant role with Mustang Bio.

    See more from Immuno-Oncology Resource Center