Immunotherapies like CAR T and bispecifics are the most exciting new therapeutic agents in myeloma therapy.  In this program, the first half of the St. Louis Myeloma Crowd Round Table held on October 16, 2021, Dr. Madhav Dhodapkar provides an overview of the concept of immunotherapy, Dr. Ivan Borrello describes some of the barriers to better outcomes, and Dr. Mark Schroeder discusses how they are being used in the clinic today.  All three take part in the audience question and answer session.

Madhav Dhodapkar, Emory University, Winship Cancer Center, Atlanta, GA: Understanding Concepts of Immunotherapy

• A primer: immune system consists of many at least 30 to 40 different kinds of cells, which protect us against pathogens [germs]
  • Innate and adaptive immune systems, specialized to recognize targets
    • Both have immunologic memory, when exposed to something, the immune system will remember 20, 30, 40, 50 years later and try to protect you
    • In cancer, immune system has capacity to evolve and adapt
  • The so-called cancer immunity cycle
    • Essentially all cancers recognized by immune system
    • All have antigens - abnormal proteins that can be recognized by the immune cell
      • If they are killed by chemotherapy, radiation therapy or surgery, etc, that creates opportunity for immune system to recognize it
      • Dying cells then are recognized by a set of cells called dendritic cells, specialized for identifying and processing those antigens
      • When these antigen presenting cells meet the T-cell it instructs the cell to make immune response to those T cells will then after they're activated
      • Goal is to get into and kill the tumor cells
      • “Brakes” that are within the immune system are suppressed by what's called checkpoints such as PD-1 and PDL
        • In solid tumors, simply taking away brakes has led to remarkable and durable responses
    • We're only at the beginning of this revolution, tackling one or two aspects of this cycle
• First Insight: Even in advanced stages, myeloma remains sensitive to immune cells
  • Even advanced relapse refractory, so-called high-risk myeloma
  • Conventional community thinking was perhaps cancer cells are too close to normal cells, making it hard for immune system to figure out normal vs abnormal
  • Even in advanced disease we can engage immune system, whether it's our own immune system or somebody else’s
  • Has potential to achieve durable responses (and even cures) by hitting the right targets in immune system
• Second Insight:  Biggest progress is not to actually cure myeloma, but to eradicate it
  • All myeloma originates from precursor stage, so even before we diagnose any patient, they have had abnormal cells in their body for at least 10 years on average with MGUS
  • Earliest stages of MGUS are recognized by immune system before any pathologist can diagnose or find cells. So the immune system is already be able to detect these, these very early immune. The problem: a 10 year period over which it evolves
  • From studies in mice, chronic infections like HIV enter phase called exhaustion, when T-cells don't work as effectively as they used to
  • As disease turns into myeloma, the T-cell’s stem cell-like features are getting depleted over time
  • Essentially imagine a situation where you have an army of people and you already you know, made them run half a marathon, and now you want them to compete in a battle. It will be better if you didn't make them run half a matter upon before you took them to battle. And that's kind of what we currently do
  • For that reason, I feel personally that the future for us, perhaps 20 years from now will be in trying to prevent MGUS and this evolution to myeloma
• Third Insight: It's all about location, location, location
  • Myeloma is multiple because it likes to grow in clusters and doesn’t like to live alone, so that they are able to form bone lesions, which, in MRIs and PETs, are called hotspots
  • Clusters create distinct spatial interactions with immune systems
  • A new concept is that when tumor cells grow together, they don't let these T-cells get in, so they need a “visa or passport” to be able to recognize the target
  • But now, only some T cells that recognize specific targets, so we can theoretically overcome this by “giving” T-cells visa or a passport by creating artificial recognition systems, such as CAR T cells or bispecific antibodies
  • Response and cure rates still not equal
  • We must create more durable responses by increasing therapy persistence
• Fourth Insight: The solution will not be one size fits all
  • Because each of us has a different immune system, which depend on HLA molecules, which are different in all us unless we have twins (two people with the exact same immune microenvironment in haven’t been found)
  • The most common CAR T target is BCMA, B-cell maturation antigen, but other CAR T are being studied
  • Other mutations are potentially targetable by to create an “engineered” immune system, that take prior therapies
• Fifth Insight: Curing, preventing, and eradicating myeloma will REQUIRE the immune system
  • It is the only system that has specific as long-term capacity for maintaining an immune response, eliminating the need to keep taking a medication that can keep adapting to the cancer

Ivan Borrello, Johns Hopkins Schools of Medicine, Baltimore, MD: Creating an Immunotherapy Treatment Strategy

• Immunotherapy is the fourth pillar treatment for cancers, historically they have been surgery, radiation, chemotherapy
• Chemotherapy is non-selective for most, it works very quickly and because it's a drug and all drugs in our body are destroyed by enzymes produced in the liver or destroyed by the kidneys, has a finite duration, doesn’t last weeks or months
• Immunotherapy is very different, it takes weeks for immunity to develop, but the good news is that it also can persist for years, hopefully a lifetime
  • Polio vaccine has immunity  when people reach 60, 70, 80; durations like that not yet in cancer
• To elicit a response a T-cell has to engage with a dendritic cell, myeloma has many of these
• So think about this as an automobile, there's a brake in an accelerator, in cancer these brakes are really, really down
  • Drugs or antibodies have been developing to “block” these brakes, which are an excess of this immunosuppressive state
• We have now gotten to the point that we can understand what these interactions are between tumors and T-cells and can regulate them in other cancers
• Two antibodies that have been developed
  • One blocks a protein called CTLA 4
  • Another blocks a protein called PD-1
  • Both are FDA approved and have really transformed the treatment of a variety of solid tumors
• A PD-1 inhibitor was not effective in myeloma, and while in myeloma right now, but I think they are important to understanding why and how the immune system can be regulated
• Other research in regulatory T cells or T regs, which as the name implies regulates cell function, will be important to understand that there is a molecular regulation
• Research in colon cancer on how the gut bacteria in the microbiome may benefit myeloma
  • A number of clinical trials about probiotics ongoing
• A healthy lifestyle is probably going to help
  • If you stay away from foods that are high in red meats, high in animal fats and more on the on the vegetable side of things, for the most part, it's going to be healthier.
  • Probiotics may have some sort of an impact
  • There's a lot of evidence to suggest that the Mediterranean diet is probably better than a northern European type of diet, certainly focused a lot more on vegetables. But you know, at least something to think about them
• Immunotherapy in myeloma
  • Immunomodulators (IMiDs) like lenalidomide (Revlimid) and pomalidomide (Pomalyst) modulate the immune system, not specifically targeting any one pathway or any one molecule, it leads to this global immune activation, iberdomide is the new generation in clinical trials
  • Antibody-based therapies - explanation at 14:30 of video
  • Antibody drug conjugates (ADCs) - chemotherapeutic agent attached to antibody (belamaf or Blenrep)
  • Bispecfic antibodies - bringing chemotherapeutic effect and T-cell to work together, targeting CD-13, effective in ALL
  • CAR T - discussion of differing types
    • Off the shelf may provide greater access, still need approval
• GVAX: “Off-the-shelf” vaccine for patients in complete remission
  • If we are not going to cure disease, we at least want to revert active disease to MGUS
  • Dr. Borrello’s lab has created a vaccine called GVAX, which is given to patients in a near complete remission, no detectable M-spike, but they still will some other aspects of the disease
  • Overall median overall survival was 7 1/2 years, but median progression free survival has not been reached
  • Definition of relapse is that M-spike has to be greater than 0.5
  • We believe we’ve been able to educate the immune system, potentially not with the strength and power of a CAR T-cell, but with a sufficient amount of memory, one of the benefits of immunotherapy that it lasts long, that we can that as this mSPIKE continues to come up, there's just enough of an immune system to push it back down, but not enough of it to completely eradicated
  • We have now opened up a large randomized trial of 50 patients
  • This could be one approach that could become an established therapy for patients that have achieved a complete response, which is very different from what we're seeing with car T cells, where the patients that have achieved the complete response of car T cells appeared to be relapsing within a year to a year and a half

Mark Schroeder, Washington University, Siteman Cancer Center, St. Louis, MO: Immunotherapies in the Clinic

• Immune system has an inflammatory and a regulatory component, some side effects are related to inflammation
• Goal with any of these treatments is to reduce the tumor burden, to get you to the lowest detectable—or undetectable—level of myeloma
• Many therapy choices targeting BCMA
• If you can’t get access to new therapy, clinical trial is an option
• CAR T procedure steps outlined beginning at 4:22-12:15
  • To be eligible, myeloma has to be under control
• Case study one: a 57 year old male had received a stem cell transplants, progressed after his transplant within two years, second transplant was not a good option
  • He was IgG Kappa, no high-risk features, but since he progressed early after transplant, he had higher chance of being less responsive to other therapies
  • He chose a BCMA-targeted CAR T and had a number of side effects in first week, solved for another week of observation before being released
  • Currently in two-year complete response, rate about 40 to 80%, but the majority of patients have cytokine release syndrome (CRS), about 20% had neurotoxicity, typically within the first two weeks
• Case study two: 74 year old male patient with refractory myeloma and IGA capital who had undergone transplant in the past year, had recently been on daratumumab and carfilzomib, but wasn't responding and light chains were rising
  • Oncologist recommended the clinical trial with this bi-specific antibody, he presented in good shape.
  • Despite feeling well to start the infusion, he rapidly experienced significant side effects soon after administration of a bispecific, as well as some neurotoxicity, but immediate treatments had him back to normal in three days
  • He was out of the hospital less than a week after this bispecific antibody therapy, MRD negative, complete response.
• Cytokine release syndrome (CRS) occurs in about 90% of CAR T and 50% of bispecfics procedures
  • Classic side effects are fever, flu like illness, muscle aches, headaches, chills
  • Some of the initial studies of car T cell therapy patients got so sick, were in the ICU, on life support, some died, but a lot was learned from those initial cases
  • Grading system helps determine treatment
  • Tocilizumab and corticosteroids are used to effectively manage CRS
• Neurotoxicity is monitored very carefully using the immune effector cell associated encephalopathy scale
  • Writing can be an early sign of neurotoxicity
  • Some cases are really extreme, where patients are having seizures, unusual, patients can be unresponsive, medical teams intervene early
• “They're very active, but not without toxicity, but the toxicities, I hope, you know, may have scared you a bit about the toxicities, but they are manageable.”
• “So who's the best patient for bi-specific?  What's the best target on the cells?  We don't know those answers yet.”

Audience Questions & Answers

• 1:57 - Dr. Schroeder, you were talking about the car T cells 90% experience, side effects, 40 to five 40 to 50% success rate. Did you have the same stats for the by specific engagers? Yeah. So the set of 10 release. Can happen in bi-specific T-cell engagers.
• 4:16 - Dr. Borrello, my question is on GVAX, is there a specific time during the treatment that this is given?  During MGUS stage, during the maintenance, right up the transplant, or is is given later?  What stage are we in?
• 6:20 - Question about treatment, planning and sequencing, because the immune system is so important to all these newer therapies.  Is there an argument to not do a chemo and stem cell procedure first, but instead to continue to treat with triplet or quad and save that and perhaps use some of the other immune based therapies and save the stem cell and chemo for a later time?
• 9:55 - For Dr. Vij, are there criteria to choose between bispecifics and CAR T?  And how many people are taking part in your trial?
• 12:46 - In 2017, I was diagnosed with multiple myeloma, achieved remission in 2018, and then last year, in 2020, developed AML.  In treatment, is either dominant right now?
• 15:22 - Would you agree that the success on the therapy is dependent on balancing the mental status of the patient with treatment?
• 16:54 - I'm a KARMMA-2 trial patient participant, just about two years past CAR T. So thank you for all your work. That leaves me with two questions and you kind of talked about it this morning.  Why do our counts linger so low for so long solo and what do we know about the durability of someone that participated early in a CAR T?
• 22:34 - I am six months post stem cell transplant. So I was really interested about the healthy lifestyle, the Mediterranean diet, the how do we go forward? And yes, you know, that fatigue is there. So it's like, okay, do I lay down and take a nap or do I have to go for a walk or do I walk my stairs?  Where do we find all this information? Or w how is it through HealthTree? Is it through certain publications or where do we get the best education, so I don't start tripping over myself and doing things wrong and then have to reeducate myself?
• 25:12 - I was unable to get stem cell because I couldn't produce enough stem cells. Is that an issue with CAR T cell procedures?
• 26:50 - Is there any scientific evidence about periodic fasting as inhibiting cancer progression?
• 28:17 - Is there still a role for allogeneic transplants or is the risk reward equation not favorable?  And then additionally do allogeneic transplants have a role in the rescue of patients after several relapses?  What is the likelihood of long-term exposure?
• 32:32 - For patients who express the BRAF mutation, what is the experience with BRAF and MEK inhibitors?
• 33:55 - I just had a transplant consolidation and now in maintenance doing great.  I am 80 years old now, perhaps the oldest patient to have a transplant in the future.  Would my age disqualify me from this?
• 33:32 - So getting into the fasting thing that was mentioned earlier,  from my limited understanding of [unintelligible] if I'm saying that correctly, is the sweet spot 48 to 72 hours, that's been proven to kill pre-cancerous cells?  Is that something in fasting that could kill cancerous cells?  And if you were to go into fasting, being in remission, would 48 or 72 hours be safe for fasting while still taking Revlimid?
• 37:14 - If you relapse on a bispecific therapy, is there any data about responding deeply to another immunotherapy like CAR T or ADCs or another bispecific?
• 41:25 - What is the data and/or clinical experience with a second autologous transplant if the first auto led to a three-year remission?
• 43:45 - Where does the myeloma cells come from?  Do they self-replicate or do they come further up the chain?  Ultimately, if theoretically, you were able to get rid of every myeloma cell in the body, would you be cured or it would be therapy latent genetic defects in stem cells or B cells?

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