[Mark]

CAR T-cell therapy for multiple myeloma

by Mark on Mon Apr 07, 2014 1:49 pm

This therapy is often discussed here. This particular study does not involve myeloma patients but I am just posting it so patients understand that this type of therapy does have risks and is likely to be used on relapsed/refractory patients for the immediate future.

"Safety concerns forced investigators at Memorial Sloan-Kettering Cancer Center to suspend patient recruitment for an early-stage study of a closely watched approach to reengineering the immune system to fight cancer. Several days ago MSK updated a site on clinicaltrials.gov to note that it was halting recruitment for a small study using T cells reengineered with chimeric antigen receptors (CARs) against CD19-positive B cells for aggressive non-Hodgkin lymphoma, triggering concerns about the potential fallout at Juno Therapeutics, the biotech formed to commercialize the effort. And Sunday evening representatives for MSK revealed at the meeting of the American Association for Cancer Research in San Diego that the deaths of two patients spurred investigators to rethink the trial protocol on recruitment, revamping the patient profile to account for the threat of comorbidities while adjusting the dose "based on the extent of disease at the time of treatment."

Heated rumors were flying on the Internet over the weekend after MSK's Michel Sadelain acknowledged the halt, citing an unexplained safety issue that popped up in discussions at AACR. In their presentation at AACR on Sunday afternoon, MSK officials noted that 10 of 22 patients in the study had died.

Six patients died of either disease relapse or progression, said MSK, while two patients died in remission from complications related to allogeneic bone marrow transplantation. An additional two patients died within two weeks of receiving a CAR-T cell infusion."

http://www.fiercebiotech.com/story/memorial-sloan-kettering-hits-brakes-engineered-t-cell-cancer-study/2014-04-06

[Multibilly]

Re: CAR T-cell therapy for multiple myeloma

by Multibilly on Mon Apr 07, 2014 3:56 pm

My heart goes out to the families of those patients that passed away during the study. It sounds like the dust is still settling regarding the complete story of what happened here.

I remember just recently reading an interview about a CAR T study based on CD19 at the University of Maryland and the City of Hope that Dr. Rapoport was leading. Was the Sloan-Kettering effort tied to those efforts or was it a different approach?

<Adding this a bit later in the day > In doing a bit more reading on the CAR T effort, I hadn't realized just how competitive the research effort around CAR T had become:

http://www.xconomy.com/seattle/2014/01/13/juno-therapeutics-adds-jeff-bezos-venrock-to-145m-venture-deal/

[Mark11]

Re: CAR T-cell therapy for multiple myeloma

by Mark11 on Sat Nov 08, 2014 12:22 pm

I just saw an article that discussed/summarized early immunotherapy and Car T cell therapy abstracts from ASH. Unfortunately, according to the article PD-1 blockers did not work for 27 myeloma patients.

'Cancer immunotherapy drugs that attack the PD-1 protein on tumor cell surfaces have made headlines for their effects on solid tumors like melanoma. But the ASH abstracts are providing some guidance how they might work against blood cancers.

The initial results seem encouraging: Some 87 percent of Hodgkin’s lymphoma patients who had failed at least three prior therapies responded to nivolumab (Opdivo) from Bristol-Myers Squibb (NYSE: BMY). Pembrolizumab (Keytruda) from Merck (NYSE: MRK) also showed early promise. (Pembrolizumab is approved to treat melanoma in the U.S., nivolumab is approved in Japan but not yet in the U.S.)

One hematological cancer that might not respond as well to PD-1 blockers is multiple myeloma. Bristol-Myers Squibb reported that none of the 27 patients with the disease responded to nivolumab. That’s a boon for Summit, NJ-based Celgene (NASDAQ: CELG), as PD-1 drugs represented a potential competitive threat to its multiple myeloma franchise."

http://www.xconomy.com/national/2014/11/07/what-early-looks-from-ash-tell-us-about-cancer-immunotherapy/

From the same article, unfortunately it appears many of the relapsed pediatric ALL patients that went into remission from CAR T cells are starting to relapse.

"Novartis (NYSE: NVS), with a program called CTL019 licensed from the University of Pennsylvania, made big news at last year’s ASH in CAR-T right around the time Juno came out of stealth mode. This year, the Penn researchers are reporting follow-up data from a study of 30 children with acute lymphoblastic leukemia that didn’t respond to chemotherapy or stem-cell transplant. At first, the treatment provoked 27 complete remissions, but that number is now down to 16 for various reasons that are detailed in the abstract. As with the other CAR-T programs, the cytokine side effects are important, and the researchers write that treatment for CRS was required in 37 percent of patients “and was rapidly reversed in all cases with the IL-6 receptor antagonist tocilizumab, together with corticosteroids in 5 patients.”"

"In other words, this particular kind of cancer immunotherapy, from research groups related to Juno, Novartis, and Kite, is moving ahead into bigger trials and more patients. The spectacular early results of the treatments aren’t sustainable over time, it seems, and there are safety concerns, but so far nothing has forced anyone to slam on the brakes."

Hopefully they will continue to make strides with respect to CAR T cells in the future so more blood cancer patients can benefit from them. It appears as if they can be part of an effective strategy for blood cancer patients but they do not seem to be a "one shot miracle cure" some patients were hoping for.

Here is a link to a discussion with an expert in immunotherapy discussing CAR T cells from the NIH.

"Medscape Medical News : Do you think it has potential to be a treatment?

Dr Bollard: While this has the potential to be a treatment, it has not yet proven to stand on its own as a single-agent curative approach, and like most therapies for cancer, it should best be considered as part of a multimodality treatment approach. The ultimate strategy would be to combine CAR T-cells with other targeted cancer treatments, such as small molecule inhibitors, antibodies, checkpoint inhibitors, etc.

Medscape Medical News: Do you see a future for this in mainstream medicine? Or will it be a therapy that will be offered only to a few very lucky patients who can access top- rate cancer clinics?

Dr Bollard: Until advances are made in the engineering of the CAR T-cells to render the technology safer, then it may be difficult for this treatment to become a mainstream therapy. Since this treatment is currently limited by its toxicity profile, numerous investigators nationally and internationally are exploring different modifications to increase the safety of the CAR T-cells. Furthermore, industry is now becoming interested in these technologies, and multicenter studies are planned. The involvement of industry is essential before these technologies will become so-called "mainstream medicine."

In addition, it is important to note that other T-cell-mediated therapies are being developed, such as the BITE antibodies and multiantigen-specific T-cells. And some of these therapies have also shown significant promise clinically for some of our patients with the poorest prognosis. Therefore, we should be open to all these developments. Breakthroughs in other lines of therapeutic development might again change the direction in which we alter our approaches for the treatment of cancer. Or add an even stronger armamentarium. Therefore, it is critical we keep an open mind.

Medscape Medical News: What about the adverse events and cytokine release syndrome, etc. Is this a big problem?

Dr Bollard: A treatment that has less immediate toxicity would definitely be desirable, especially considering the concern that very sick patients are being treated with this therapy and developing life-threatening toxicities that would be considered far more severe than is typically seen with chemotherapy or even with bone marrow transplantation. Therefore, while the results from the CD19-CAR T-cell studies are indeed promising, we have to carefully watch for these extreme toxicities. Furthermore, we are still waiting for the long-term efficacy data, and it is still too early to say whether or not CD19-CAR T-cells offer a potentially curative treatment.

In addition, one potential problem with CD19-CAR T-cell therapy is the limitation of targeting a single-surface antigen, especially as highlighted by the proportion of patients (10%) who relapsed with CD19-negative acute lymphoblastic leukemia. This emphasizes that, for those patients, you only get one chance with this therapy, and explains why the Leukemia Lymphoma Society has funded groups at Children's National and Baylor College of Medicine to focus on a multiantigen T-cell therapy for patients with ALL to avoid this immune escape mechanism."
http://www.medscape.com/viewarticle/833373#vp_1

[Mark11]

Re: CAR T-cell therapy for multiple myeloma

by Mark11 on Thu Feb 19, 2015 11:30 am

I just saw this article using CAR T cells targeting CD138 for relapsed myeloma patients. Only 5 patients received the therapy. Unfortunately the responses are not nearly as dramatic as the anti CD19 CAR T's are for ALL (acute lymphoblastic leukemia) patients.

G Bo, "CD138-directed adoptive immunotherapy of Chimeric Antigen Receptor (CAR)-modified T cells for Multiple Myeloma," Journal of Cellular Immunotherapy, Feb 2015 (link to abstract)

"Five patients diagnosed with chemotherapy-refractory multiple myeloma were enrolled into this trial, although one later advanced to plasma cell leukemia. By intravenous infusions, these patients received CD3+ CART-138 cells in an escalating dose. No intolerable toxicity was observed during this process. CART-138 cells were expanded to a level 1,000 times higher than the initial engraftment level and were maintained in the peripheral blood. In addition, increased CART-138 cells were also detected in the bone marrow. Four of the five patients had stable disease (SD) longer than three months, and one patient with advanced plasma cell leukemia had a reduction of the myeloma cells in her peripheral blood (from 10.5% to <3%)."

[Mark11]

Re: CAR T-cell therapy for multiple myeloma

by Mark11 on Sat Mar 07, 2015 11:57 am

Here is another journal article about CAR T cells. It is a little difficult to follow but not as technical as some.

I thought this was an interesting point about autologous T cells being exposed to chemo­therapy while allogeneic T cells are not.

Given that allo-HSCT, being the most successful type of adoptive therapy, requires timely acquisition of hematopoietic stem cells from the more appropriate donor, the gene-modification using autologous lymphocytes from cancer-bearing patients, not requiring donors, can provide the higher clinical versatility. On the other hand, gene-modification of allogeneic T cells from an allo-HSCT donor for DLI is greatly advantageous to employ chemo-naïve healthy T cells.

Hopefully they keep making progress with respect to this technology and hopefully the myeloma docs can find a good target for this therapy for myeloma patients!

Mark

Article citation:

H Fujiwara, "Adoptive Immunotherapy for Hematological Malignancies Using T Cells Gene-Modified to Express Tumor Antigen-Specific Receptors," Pharmaceuticals, Dec 15, 2014 (link to full text html, link to full text PDF)

Abstract:

Accumulating clinical evidence suggests that adoptive T-cell immunotherapy could be a promising option for control of cancer; evident examples include the graft-vs-leukemia effect mediated by donor lymphocyte infusion (DLI) and therapeutic infusion of ex vivo-expanded tumor-infiltrating lymphocytes (TIL) for melanoma. Currently, along with advances in synthetic immunology, gene-modified T cells retargeted to defined tumor antigens have been introduced as “cellular drugs”. As the functional properties of the adoptive immune response mediated by T lymphocytes are decisively regulated by their T-cell receptors (TCRs), transfer of genes encoding target antigen-specific receptors should enable polyclonal T cells to be uniformly redirected toward cancer cells. Clini­cal­ly, anticancer adoptive immunotherapy using genetically engineered T cells has an impressive track record. Notable examples include the dramatic benefit of chimeric antigen receptor (CAR) gene-modified T cells redirected towards CD19 in patients with B-cell malignancy, and the encouraging results obtained with TCR gene-modified T cells redirected towards NY-ESO-1, a cancer-testis antigen, in patients with advanced melanoma and synovial cell sarcoma. This article overviews the current status of this treatment option, and discusses challenging issues that still restrain the full ef­fec­tive­ness of this strategy, especially in the context of hema­tolo­gical malignancy.

[Mark11]

Re: CAR T-cell therapy for multiple myeloma

by Mark11 on Thu Apr 23, 2015 7:36 am

I saw this article this morning with respect to this topic. It does mention myeloma.

In one of these presentations, the authors hypothesized that infusion of genetically modified tumor-specific T cells following autologous stem cell transplant (ASCT) may overcome various barriers in treating multiple myeloma (multiple myeloma). These barriers include antigen specificity, low levels of target expression, and failure to break self-tolerance.

“[Our] data show that NY-ESOc259-T cells exhibit robust trafficking and expansion, durable persistence without exhaustion, and follow a natural immune expansion and contraction pattern consistent with an antigen-driven mechanism of action,” the authors indicated. “Relapse correlated with a loss of persistence or tumor antigen escape, suggesting that targeting multiple antigens and maintenance infusions may increase durable remissions.”"

Source: "AACR Special: Serial Killer Cells on the Side of the Angels - Researchers Discuss Strategies to Improve the Safety and Effectiveness of Reengineered T cells in Eradicating Tumors", Genetic Engineering & Biotechnology News, Apr 22, 2015 (link to full text of article)

[Tracy J]

Re: CAR T-cell therapy for multiple myeloma

by Tracy J on Thu Apr 30, 2015 9:14 am

Have you seen the current issue of the preeminent peer-reviewed journal Science? The major topic is immune therapy in cancer. There's a whole big review piece on engineered T cell therapy for lots of different cancers. This is big stuff!

[Mark11]

Re: CAR T-cell therapy for multiple myeloma

by Mark11 on Thu May 21, 2015 7:11 pm

Here is a link to an ASCO abstract about the first 3 patients that received CTL019. Congrats to Beacon Medical Advisor Dr. Adam Cohen for being one of the co-authors of the study.

"Methods: multiple myeloma patients are eligible if they experienced disease progression within one year of a prior autologous stem cell transplantation (ASCT) and are medically fit to undergo second ASCT. Study therapy consists of 1-5x107CTL019 cells infused 12-14 days after high-dose melphalan + ASCT. Results: 4 subjects have been treated and have completed 30-220 days of follow-up. Median prior lines of therapy is 7.5 (range 3-10). 3/4 have unfavorable cytogenetics; 1/4 had PC leukemia. Adverse events have included hypogammaglobulinemia (4/4) and grade 1 cytokine release syndrome (1/4). 3 subjects are evaluable for response. In all 3 subjects, CTL019 engraftment was achieved (peak 0.1-0.6% of peripheral blood T cells at days 30-42), and B cells were not detectable by flow cytometry in blood or marrow at day 42. At day 100, subject #1 attained MRD-negative stringent complete response (CR), and Subject #2 attained MRD-negative unconfirmed (due to unevaluable bone marrow core) CR. Response duration in Subject #1 has surpassed the response duration after this subject’s prior ASCT (i.e., remission inversion). 99.95% of Subject #1’s multiple myeloma PC were CD19-negative by flow cytometry and RTPCR, indicating that efficacy in this subject is not due to direct cytotoxicity of CTL019 against the dominant multiple myeloma PC population. Subject #3 experienced disease progression at day 43. Updated results on the first 5 subjects will be presented. Conclusions: Preliminary data suggest that CTL019 can be manufactured from and safely administered to refractory multiple myeloma patients. CTL019 can engraft and induce B cell aplasia after salvage ASCT. Ongoing, deep responses in 2 of 3 evaluable subjects are encouraging with respect to potential efficacy."

http://abstracts.asco.org/156/AbstView_156_145682.html

[Mark11]

Re: CAR T-cell therapy for multiple myeloma

by Mark11 on Thu Jun 25, 2015 1:53 pm

I thought I would add this article to this thread. It is a business article as opposed to a scientific paper. MikeB brought up the issue of how pharmaceutical companies could potentially profit from this type of therapy in the Beacon news article about CTL019. Here is an article discussing this topic. Note this article says the cost of a treatment with CAR T cells costs $75,000 to manufacture as opposed to the $20,000 that I had seen previously.

"If a half-dozen academic centers hadn’t built specialized clean rooms like this one, there wouldn’t be any clinical trials, or any IPOs. But Jensen’s center is no commercial operation: it can prepare cells for only 10 patients a month. It costs $75,000 to manufacture cells for each one."

Also note the importance of persistence of the cells for on going protection and that the Beacon news article mentions that CTL019 did not persist in the myeloma patients like they do for some of the ALL and CLL patients.

"The goal is to find the next CD19. But that’s not easily done. Since few antigens appear only on tumor cells, any targeted T cell runs the risk of wiping out vital organs, as happened to the colon cancer patient in 2009. The Recombinant DNA Advisory Committee, a federal body that oversees gene therapy, called a meeting this June to debate how scientists planned to avoid these and other side effects. One way to lessen the risk is already being tested in patients: “suicide switches,” which let doctors rapidly kill off all the engineered T cells should any serious problems arise. This spring, Michael Jensen, a pediatric cancer doctor at Seattle Children’s whose cell-therapy center treated Wright, opened a study to treat neuroblastoma, the most common cancer affecting infants. He says T cells will target an antigen found on nerve cells. If the T cells do unexpected damage, they can be inactivated with a dose of the drug Erbitux.

Safety isn’t the only obstacle. How can engineered T cells be made to persist in a person’s body to provide permanent protection? So far they don’t seem to linger in many patients, something Frohlich terms a “big problem.” And dense organ tumors can saturate their surroundings with signals, like a molecule called PD-L1, that turn T cells off. This defense is the process that checkpoint inhibitors, the new immunotherapy drugs sold by Merck and Bristol-Myers Squibb, interfere with. But DNA engineering may offer clever solutions as well. Jensen says he rewired the DNA of T cells so this “off” signal instead provokes them to kill even more."


http://www.technologyreview.com/featuredstory/538441/biotechs-coming-cancer-cure/


Link to Beacon news article.

https://myelomabeacon.org/news/2015/06/04/car-t-cell-therapy-multiple-myeloma/

[mikeb]

Re: CAR T-cell therapy for multiple myeloma

by mikeb on Sat Jun 27, 2015 11:02 pm

Hi Mark,
Thanks for the link. That was an informative article. It sounds like the pharma companies don't exactly know the answer to the question I asked, or at least aren't ready to share the answer yet.

It will be very interesting to see how this technology evolves/matures over the next few years.

Mike