More on the Juno JCAR015 deaths..

By now many of you have seen the news in much of the mainstream about the death of two patients from cerebral edema in Juno’s JCAR015, a.k.a., “ROCKET” clinical trial, especially as Wednesday’s finanacial news highlighted the precipitous drop in Juno Therapeutics’ stock.

The links below are my attempt to look past the headlines for analysts’ reactions, and to gain a better understanding of why this may have happened, and what this means for the future of CAR-T.  I am particularly interested, as the CAR-T trial I underwent last year was in fact one of Juno’s.  (It may have been JCAR014, but I would need to look it up.)


An analyst’s commentary, followed by some interesting reader comments…
More Juno CAR-T Deaths | In the Pipeline


Another analyst’s commentary…
Two more patients die as Juno’s lead CAR-T turns lethal again; trial halted – ENDPOINTS NEWS


MSNBC Analyst on JUNO: “This is just a short setback” (video)


Matthew Herper has been covering this territory for Forbes for awhile now…
Five Lessons From Today’s Pharma Failures


An overview of Juno’s And Kite Pharma’s various CAR-T trials…
TwitLonger — When you talk too much for Twitter


Comparisons of Juno’s JCAR015 vs. JCAR017 vs. Kite KTE-C19 vs. Novartis CTL019:
EP Vantage – Why this could be strike three for Juno’s lead


“…Kite believes its interim data of the Phase II trial released in September will be strong enough to lead regulators at the FDA to ultimately give its approval – making KTE-C19 the first CAR-T therapy to reach the market ahead of rivals Juno and Novartis (NVS). Kite said it plans to seek regulatory approval of KTE-C19 in diffuse large B-cell lymphoma (DLBCL), transformed follicular lymphoma (TFL) and primary mediastinal B-cell lymphoma (PMBCL), based upon the combined data of multiple trial cohorts. Kite anticipates commercial launch of KTE-C19 in 2017…”

Juno Halts CAR T Trial for Second Time Following Additional Patient Deaths


“…Kite is currently in pole-position among the competitors, and plans to file its KITE-C19 in 2017.  However despite its encouraging data, it also causes severe side-effects, and has seen patients deaths in trials linked to the treatment.

“In CAR-T, T cells are genetically engineered to attack the B cells that become malignant in some blood cancer types, and it is this unleashing of the immune system which can cause major problems, and is still poorly understood.

“Following the success of immunotherapies such as the PD-1 checkpoint inhibitors,  CAR-Ts are seen as the next big thing – but the latest news is just another reminder that these drugs carry much higher risks than drugs such as Merck’s Keytruda and BMS’ Opdivo…”

Juno halts CAR-T trial again after 2 more deaths – Pharmaphorum


CAR-T in the news (Week Ending 11/19/16)

CAR-T business news:

  1. Kite details filing plans for lead CAR-T | BioPharma Dive 
  2. Kite Pharma to keep anticipated CAR-T launch ‘controlled’ and targeted at certain hospitals – Medical Marketing and Media
  3. CAR-T cells forge ahead, Novartis reorganizes : Nature Biotechnology : Nature Research

One problem with current CAR-T therapies is, they require individualized collection and “manufacturing” of one’s own T cells.  This is an extremely expensive process that would likely severely inhibit widespread access to these potentially life-saving therapies once they exit clinical trials and gain FDA approval.

Thus there is ongoing research into using “off-the-shelf” pre-manufactured allogeneic T cells (i.e., T cells from other healthy donors) rather than one’s own collected T Cells.  Cellectis, in Suresnes, France, has been running clinical trials on a “Universal CAR-T” cell. Below are some other news items on that front that I came across this week:

  1. Cell Medica signs up for an off-the-shelf CAR-T collaboration with Baylor – ENDPOINTS NEWS
  2. Multiplex genome editing to generate universal CAR T cells resistant to PD1 inhibition | Clinical Cancer Research

T cells can become “exhausted”?  Improving CAR-T cells’ exhaustion:
Insight into tired immune cells opens door for cancer therapy

 

CAR-T Follicular Lymphoma Patients Who Achieve a Complete Response Have a Durable Remisison

Here is some good news I learned from Dr. Steven Schuster (one of the gurus in CAR-T) during a November 17, 2016 Lymphoma Research Foundation “Advances in Immunotherapy in the Treatment of Lymphoma” teleconference Q&A. This teleconference is posted at http://www.cancercare.org/connect_workshops/555-advances_immunotherapy_treatment_lymphoma_2016-11-17

Results from his UPENN Abramson Comprehensive Cancer Center follicular lymphoma CAR-T clinical trial showed:

  • Of 14 follicular lymphoma patients 10 (72%) achieved a complete remission.
  • No patient achieving a CAR-T complete remission has relapsed.
  • As of today the average time in complete remission is about 2 years.
  • If your complete remission is 2 years or greater you have the same survival odds as someone who never had follicular lymphoma.
  • After one year about 50% of his follicular lymphoma CAR-T patients have their non-lymphoma B-cells come back and no longer need IVIG infusions.

Teleconference – Advances in Immunotherapy in the Treatment of Lymphoma

I know this is short notice (the teleconference takes place tomorrow), but my wife just received an email invitation to this Lymphoma Research Foundation (LRF) teleconference yesterday.  The speakers include Dr. Bruce D. Cheson at Georgetown U. Hospital, and Dr. Stephen J. Schuster at U. Penn Hospital.  Both physicians are currently running CAR-T clinical trials for lymphoma patients, and I almost enrolled with Dr. Schuster in early 2015.

Advances in Immunotherapy in the Treatment of Lymphoma
Thursday, November 17, 2016, 1:30 PM to 2:30 PM EST

 

Week ending 11/6/2016 (CAR-T abstracts from upcoming ASH 2016)

The abstracts for the annual American Society of Hematology (ASH) conference in December were published a couple of days ago, and are available here. In my quick search of abstracts relevant to CAR-T and FL, I’ve highlighted the following:

From a study at U. Penn that I almost enrolled in, after meeting with Dr. Stephen Schuster, chief of Lyphoma Services, for almost two hours in February 2015.  At the time, they had treated 5 FL patients with CAR-T, all of whom had achieved Complete Remissions (CR’s).  We hadn’t seen this success with FL patients anywhere else, so it was difficult for me to decline the last remaining spot and enroll at Memorial Sloan-Kettering in NYC instead, which I did only because it is much closer to home.  (As I understand it, I am MSK’s first FL patient to complete CAR-T.)

In this latest update to the study, 9 of 14 FL patients have now achieved a CR.  For me, the takeaway is that those who achieve a CR are still remaining in CR:
Chimeric Antigen Receptor Modified T Cells Directed Against CD19 (CTL019) in Patients with Poor Prognosis, Relapsed or Refractory CD19+ Follicular Lymphoma: Prolonged Remissions Relative to Antecedent Therapy

Also from U. Penn, results of this study will be presented by Dr. Schuster himself.  Not specific to FL, although transformed FL patients are included.  I love this sentence towards the end of the Results section: “To date, no pt achieving CR has relapsed.
Treatment with Chimeric Antigen Receptor Modified T Cells Directed Against CD19 (CTL019) Results in Durable Remissions in Patients with Relapsed or Refractory Diffuse Large B Cell Lymphomas of Germinal Center and Non-Germinal Center Origin, “Double Hit” Diffuse Large B Cell Lymphomas, and Transformed Follicular to Diffuse Large B Cell Lymphomas

An attempt to mitigate Cytokine Release Syndrome (CRS) in CAR-T, which can be quite dangerous and remains a serious barrier to more widespread application:
Ruxolitinib Prevents Cytokine Release Syndrome after CART Cell Therapy without Impairing the Anti-Tumor Effect in a Xenograft Model

From Dr. Kochenderfer, et al, at the NCI in Bethesda, MD: “Humanized” CAR-T cells (as opposed to the typical murine (mouse-derived), attempting to enhance the persistence of the infused CAR-T cells:
T Cells Expressing a Novel Fully-Human Anti-CD19 Chimeric Antigen Receptor Induce Remissions of Advanced Lymphoma in a First-in-Humans Clinical TrialClinically Relevant Abstract 

From the Fred Hutchinson Cancer Center (“Hutch”) in Seattle: An attempt to mitigate CRS in CAR-T by  infusing “CD4+ and CD8+ T cell subsets … in a 1:1 ratio”:
Biomarkers of Cytokine Release Syndrome and Neurotoxicity after CD19 CAR-T Cells and Mitigation of Toxicity By Cell Dose

Depleting CAR-T cells that are “too persistent”:
Depleting CAR T cells after tumor treatment reverses B cell deficiency in mice

 

Financial:

ASH preview – a low-key damp squib for cell therapies (financial summary of CAR-T at ASH)
Kite Pharma at ASH
Juno Therapeutics at ASH (conducted my CAR-T at MSK)
The trials of Juno
Novartis promises a speedy CAR-T pitch, boasts about its slate of blockbusters-to-be

Miscellany:

A nice glossary:
Lymph Nodes: Locations and Functions

Some recent CAR-T coverage on OncLive:
CAR T-Cell Therapy Continues to Show Promise in Non-Hodgkin Lymphoma
From Hospice to Remission: Hopes Remain High for CAR Therapies

I don’t know how I came across this, but it seems to have some useful information for newly-diagnosed Lymphoma patients:
https://www.verywell.com/lymphoma-and-leukemia-4014692