[Beacon Staff]

Re: CAR T-cell therapy for multiple myeloma

by Beacon Staff on Wed Sep 09, 2015 6:20 pm

The University of Pennsylvania has issued a press release with in­for­ma­tion about its ex­peri­mental CTL019 CAR T-cell therapy. It discusses a recently published case report involving a myeloma patient who had received 9 previous therapies, but went on to achieve a complete response after having a stem cell transplant followed by CTL019 treatment.

Here is a link to the full press release. Here are the first few paragraphs:

A multiple myeloma patient whose cancer had stopped responding after nine different treatment regimens ex­peri­enced a complete remission after receiving an investigational per­son­al­ized cellular therapy known as CTL019 developed by a team at the University of Pennsylvania. The inves­ti­ga­tional treatment was combined with chemotherapy and an autologous stem cell transplant – a new strat­egy designed to target and kill the cells that give rise to myeloma cells.

The team’s findings are published in a case report today in the New England Journal of Medicine. Prior to receiving the therapy, the patient had already received nine different therapy regimens in the five years since her diagnosis, including a previous autologous stem cell transplant, which had only controlled her disease for a few months. Her bone marrow was almost entirely filled by cancerous cells when she entered the study. By 130 days after receiving the infusion of engineered cells, tests revealed no evidence of disease. The patient – who was the first to be treated as part of this trial – remains in remission more than 12 months after receiving this therapy.

The new report expands on data that were presented during the American Society of Clinical Oncology meeting in June 2015 about the first five myeloma patients to receive CTL019, which was tested in trials for leukemia beginning in 2010. Now, the Penn researcher team also report updates on the myeloma trial’s overall progress: Of ten patients who have received the therapy to date, six remain progression-free, though two patients have only very recently been treated.

Reference:

AL Garfall, "Chimeric Antigen Receptor T Cells against CD19 for Multiple Myeloma," The New England Journal of Medicine, Sep 10, 2015 (abstract)

Recall that The Beacon wrote a detailed article discussing the UPenn trial – and CAR T-cell therapy in general – this summer. Here is a reference to it:

"CAR T-Cell Therapy For Multiple Myeloma: Promising Signs Of Efficacy (ASCO 2015)," The Myeloma Beacon, June 4, 2015.

[Mike F]

Re: CAR T-cell therapy for multiple myeloma

by Mike F on Thu Sep 10, 2015 2:18 pm

Just read that article in the New England Journal of Medicine. The response in that patient was pretty amazing, and with next to nothing in the way of side effects.

As a note of caution, though, the responses in their other patients have not been as impressive with a couple of partial responses and one VGPR. Still not bad given that (at least as I read it) all of these patients are high risk, all have progressed after a prior autologous stem cell trans­plant and several other lines of therapy.

[Mark11]

Re: CAR T-cell therapy for multiple myeloma

by Mark11 on Fri Sep 18, 2015 4:42 pm

Hi Ping,

There are some trials without use of high dose chemo (auto), though immunotherapy does pair well with high dose chemo in blood cancer. Here is one at the NIH that uses Cytoxan and fludarabine prior to anti BCMA CAR T's:

https://clinicaltrials.gov/ct2/show/NCT02215967

Here is one at Penn that does not appear to be using any chemo prior to anti BCMA CAR T.

https://clinicaltrials.gov/ct2/show/NCT02546167

Mark

[Mark11]

Re: CAR T-cell therapy for multiple myeloma

by Mark11 on Thu Oct 01, 2015 4:21 pm

Not surprisingly immunotherapy will top the agenda for this years ASH meeting. Let's hope we hear some positive news about immunotherapy for myeloma at this year's meeting!

Immunologic Treatments of Hematologic Malignancies: Moving Beyond Salvage Therapy to Curative Eradication of Minimal Residual Disease


Recent advances in the field of immunology, including immune evasion, genetic engineering, and adoptive immunotherapy, have generated novel immune-based strategies and improved the utility of existing options, such as allogeneic hematopoietic stem cell transplantation (HSCT). These new approaches offer vast clinical promise to impact a wide array of diseases, including acute myeloid leukemia (AML), acute lymphoid leukemia (ALL), Hodgkin and non-Hodgkin lymphoma, and myeloma, as well as non-malignant hematologic disorders such as sickle cell anemia and other inherited hematologic or metabolic diseases.

Among the most exciting emerging therapies are T-cell checkpoint inhibitors, which non-specifically amplify immune responses and therefore have significant off-target events. Antibody-based therapies interfere with inhibitory receptors, such as the PD-1 receptor on T cells and its ligand PDL-1/2 on either cancer cells or in the microenvironment. Because these monoclonal antibodies unleash exhausted T cells to respond to tumors with potent efficacy and strong clinical profiles, they may provide valuable new therapeutic options to transform patient care in hematologic cancers.

Another highly promising emerging area is engineered adoptive T-cell cell therapy, with compounds demonstrating therapeutic activity against a broad variety of lymphoid malignancies. To produce these therapies, the patient’s or donor’s T cells are engineered ex vivo to express a recombinant chimeric antigen receptor (CAR) with an extracellular antibody-derived domain for binding with a tumor-specific antigen (TSA) and an intracellular component of a T-cell receptor (TCR)-derived signaling moiety for T-cell activation. This CAR T-cell approach harnesses the potent T cell cytolytic mechanisms directed by the specificity of the antibody domain, allowing for the use of T cells in a specific, but major histocompatibility complex (MHC)-unrestricted, manner. Recent studies have demonstrated significant and durable efficacy using these studies to produce curative results in specific patient populations, which researchers aim to replicate in additional settings.

These important developments have driven new perspectives on how to manipulate the immune system with the goal of curing hematologic diseases that have historically been deemed fatal. Today there are exciting research opportunities to expand the utility of these novel approaches in the near term and support their implementation far beyond hematologic diseases in the future.


http://www.hematology.org/Research/Recommendations/Research-Agenda/3822.aspx

[Mark11]

Re: CAR T-cell therapy for multiple myeloma

by Mark11 on Mon Nov 16, 2015 10:28 am

Some good news from a late breaking anti BCMA CAR T cell trial that was conducted at the NIH for ASH 2015.. I had mentioned previously that it seemed like BCMA would be a better target for myeloma than CD19. I had mentioned this trial at the NIH in previous posts as one that late stage patients should check into. Only 2 patients treated at the highest dose level so far. Not much response at the lowest dose levels. It is early and so we do not know if these will prove durable, but this seems to be a move in the right direction.

"Of the 6 patients treated on the lowest 2 dose levels, one patient had a transient partial remission (PR) of 2 weeks duration; the other 5 patients had responses of stable disease (SD). On the 3rddose level, 2 patients obtained responses of stable disease, and one patient obtained a response of very good PR (VGPR) with complete elimination of multiple myeloma bone disease on positron emission tomography (PET) scan, normalization of serum free light chains, and clearance of bone marrow plasma cells. Toxicity among patients on the first 3 dose levels was mild and included cytopenias attributable to chemotherapy, fever in 3 patients, and signs of cytokine release syndrome including tachycardia and hypotension in Patient 8 who had a VGPR.

Two patients have been treated on the highest dose level of 9x106CAR+ T cells/kg. The first patient on this dose level, Patient 10, had multiple myeloma making up 90% of total bone marrow cells before treatment. Starting 4 hours after infusion of CAR T cells, Patient 10 exhibited signs of cytokine release syndrome including fever, tachycardia, dyspnea, acute kidney injury, coagulopathy, hypotension requiring vasopressor support, and muscle damage manifesting as an elevated creatine kinase level and weakness. His neutrophil count was less than 500/µL before the CAR-BCMA T-cell infusion and remained below 500/µL for 40 days after the CAR T-cell infusion before recovering. He also experienced prolonged thrombocytopenia. Patient 10’s myeloma was rapidly eliminated after CAR-BCMA T-cell infusion. By immunohistochemistry staining for CD138, bone marrow plasma cells decreased from 90% before treatment to 0% one month after the CAR T-cell infusion. The serum M-protein decreased from 1.6 g/dL before treatment to undetectable 2 months after treatment. The serum and urine immunofixation electrophoresis tests were negative 2 months after the CAR T-cell infusion. Patient 10’s current myeloma response is stringent complete remission.

The second patient treated on the 9x106CAR+ T cells/kg dose level, Patient 11, had IgG lambda multiple myeloma with 80% bone marrow plasma cells before treatment. Patient 11 experienced signs of cytokine release syndrome with toxicities including fever, tachycardia, hypotension, delirium, hypoxia, and coagulopathy. Patient 11’s M-protein decreased from 3.6 g/dL before treatment to 0.8 g/dL 4 weeks after treatment. His serum lambda free light chain decreased from 95.9 mg/dL before treatment to 0.15 mg/dL 4 weeks after treatment. Four weeks after CAR T-cell infusion, bone marrow plasma cells were undetectable."

https://myelomabeacon.org/resources/mtgs/ash2015/abs/lba-1/

[Mark11]

Re: CAR T-cell therapy for multiple myeloma

by Mark11 on Wed Dec 02, 2015 9:19 am

A short interview with the CEO of Cellectis. The company has been in the news recently due to their allogeneic CAR T product putting a baby with leukemia into remission. Very realistic and definitely a "hype free" interview.

Q. "CAR-T seems to be extremely hype right now. At BIO-Europe 2015, I had the impression everybody was talking about CAR-T. Do you think it could have the same impact as monoclonal antibodies?

A. What’s interesting with CAR-T is that you can target cells which expresses less receptors (10k receptors instead of 100k for monoclonal antibodies). This increases the targets for CAR-T and the possibilities linked.

But there are also downsides. Tissues with low expressions can become targets too and CAR-T cells would start attacking healthy cells.

People should not overemphasise CAR-T. We are still at the beginning of the beginning of this technology. And it will probably have to be combined with surgery or checkpoint inhibitors.

Q. You seem pessimistic about CAR-T…?

A. I am just trying to be more realistic, even though I am super positive about the technology. It will bring something really great to haematology field, but is not a cure for cancer. It’s more of a long-haul race in the right direction as opposed to fast results, and we expect great things perhaps 20 years down the line as opposed to 2016.

But yes, it will probably not be the miracle product some people are talking about."

[Mark11]

Re: CAR T-cell therapy for multiple myeloma

by Mark11 on Fri Dec 04, 2015 4:44 pm

This is a good paper recently published about immunotherapy for myeloma. It is really a good read for those interested in immunotherapy.

I am just going to post the part that describes the immune dysfunction of a myeloma patient. You can see why it is so difficult for an immunotherapy other than allogeneic transplant to be effective against myeloma, given that a myeloma patients own immune system is not the best platform to launch an immune attack.

"Multiple myeloma (multiple myeloma) is the second most common hematologic malignancy, with an estimated 26,850 cases to be diagnosed in 2015 in the United States.1 The disease is characterized by clonal expansion of malignant plasma cells, and associated clinical sequelae that may include skeletal lesions, renal failure, anemia, and hypercalcemia. multiple myeloma is associated with progressive immune dysregulation, resulting in a tumor microenvironment that promotes disease tolerance and progression. B-cell dysfunction is characterized by immunoparesis—hypogammaglobulinemia of the uninvolved immunoglobulins—and increased susceptibility to infections due to viruses and encapsulated bacteria. Disease evolution is associated with defects in T-cell immunity, natural killer (NK) cell function, and the antigen-presenting capacity of dendritic cells (DCs). The T-cell repertoire is characterized by the selective loss of myeloma-specific lymphocytes. A concomitant rise in suppressor cells, including regulatory T cells and myeloid-derived suppressor cells, is observed in the peripheral blood and within the bone marrow microenvironment. Immune checkpoint pathways that help maintain immune equilibrium in health are upregulated in the presence of malignant plasma cells, fostering a state of immune tolerance. The upregulation of negative costimulatory signals induces a state of T-cell exhaustion. This blunts T-cell activation and expansion, and blocks T-cell–mediated killing of myeloma targets. In addition, myeloid and plasmacytoid DCs have been shown to accumulate in the bone marrow of multiple myeloma patients, where they can paradoxically protect myeloma tumor cells from cytotoxic CD8+ T lymphocytes, thus playing a dual role in cellular antimyeloma immunity."

http://www.hematologyandoncology.net/index.php/archives/november-2015-3/immune-therapy-in-multiple-myeloma/


There has been some interesting discussion over in this thread about how ELO stimulates NK cells.

https://myelomabeacon.org/forum/fda-approval-empliciti-elotuzumab-t6426-10.html

CS1 is the target for ELO and that is expressed on both myeloma cells and T cells. Note what happened when using a CAR T cells with CS1 as the marker.

"Antigenic escape is indeed one of the major limitations of CAR T-cells directed against a single antigen on the tumor cells. Preclinical work aiming to overcome this problem has been conducted in which multiple myeloma patients’ T cells were transduced with lenti-CAR vectors targeting several known multiple myeloma surface antigens: CS1, CD317 (HM1.24), CD138, and BCAM. Interestingly, CS1 and CD317 were also expressed on T cells and led to SELF-KILLING OF THE CAR T CELLS THEMSELVES, likely limiting the use of these antigens in further development of antimyeloma CAR T cells."

[Mark11]

Re: CAR T-cell therapy for multiple myeloma

by Mark11 on Sat Dec 05, 2015 10:31 am

I usually try and avoid posting YouTube videos and stick, instead, to peer-reviewed journal articles, but I thought it would be interesting to post Dr. Kochenderfer's presentation at ASH with regard to the BCMA CAR T trial at the NIH. I have been mentioning BCMA as a potential target for a while so I am glad to see it show the ability to put a patient into remission. This is an oral presentation about the abstract posted above.

[Mark11]

Re: CAR T-cell therapy for multiple myeloma

by Mark11 on Sun Feb 14, 2016 6:54 pm

Here is a nice review of potential immunotherapies for myeloma. It goes into some different targets that could prove helpful. Good read for those interested in immunotherapy, in my opinion:

AO Ayed et al, "Immunotherapy for multiple myeloma: Current status and future directions," Critical Reviews in Oncology Hematology, December 2015 (full text of article)

Abstract:

Multiple myeloma (M​M) is a plasma cell neoplasm which constitutes about 10% of all hematologic malignancies and has been in the limelight of fast-track development of novel drugs that have contributed to the transformation of a rapidly lethal disease into a chronic illness with significant improvement in quality of life. Nonetheless, M​M remains an incurable disease in many patients. Immunotherapy has been one of the approaches that had the highest hope for curing this disease. More than two decades of research and clinical trials in immunotherapy for M​M have however resulted in very little impact on patient survival. The various immunotherapy approaches that have been attempted over the last two decades but were fraught with failure have already been extensively summarized in many published reviews. Nevertheless, in view of better understanding of the immune checkpoints, the innate immune system, and improved biotechnology, there is renewed hope. In this review, we will briefly discuss the unsuccessful approaches and emphasize the lessons learned, highlight the challenges that lie ahead, and discuss the more promising approaches, that already exist or being developed such as use of allogeneic stem cell transplants (allo-SCT) as a form of cellular immunotherapy, new monoclonal antibodies, chimeric antigen receptor (CAR) T-cell adoptive therapy, and NK cell therapy.

[Mark11]

Re: CAR T-cell therapy for multiple myeloma

by Mark11 on Thu Mar 03, 2016 10:07 pm

Interesting article about immunotherapy I saw online.

"The Most Promising Cancer Therapy in Decades Is About to Get Better (Tumors contain the seeds of their own destruction. We just need to work out how to activate them)", The Atlantic, March 3, 2016 (full text of article)

This article does a nice job of discussing why "targeted therapies" tend to only be effective for short time periods. It also shows why an ideal target is necessary. Unfortunately we do not know what the ideal target or targets are for myeloma.

Here's an extended excerpt from the article:

As cancers develop, they also evolve and diversify. Cells on one side of a tumor can end up with very different mutations (and neo­antigens) from those just centimeters away. This concept, known as ‘hetero­geneity,’ partly explains why the war against cancer has been so entrenched. Consider the much-vaunted “targeted therapies” – drugs that go after mutations specific to a patient’s cancer. If those mutations are found only in some parts of a tumor, the treatment will leave a reservoir of cells that can grow anew, or even evolve resistance to the drug. That’s why many people get great results with targeted therapies, but then rebound within a few months.

Heterogeneity matters to the immune system, too. Some mutations develop early on in a tumor’s life and are found in all of its cells. Let’s call them trunk mutations. Others are late­comers and found in just a fraction of the tumor cells. Those are the branches.

Quezada and Swanton’s teams found that patients had better survival rates if their tumors have lots of trunk neoantigens, but not branch ones. They also responded better to pembro­lizumab, one of those checkpoint inhibitors that works by un­leash­ing the immune system (and the drug Jimmy Carter recently took). The team studied 34 patients and found that almost everyone whose tumors had a wide trunk and sparse branches responded well to the drug. By contrast, the poorest responders almost all had thin trunks and luxuriant branches. They found the same pattern among 64 melanoma patients treated with two different drugs.

This makes total sense. The immune system only has a limited armada of T-cells at its command. If it deploys these against branch neo­antigens, it is “wasting resources on the branches,” says Quezada. And you can’t chop down a tree by pruning back the branches. You need to go after the trunk. “Our data tell us with absolute certainty that if we want to target every single cell on the tumor, we need to find the trunk mutations.”