Urologic Oncology

SLIDES & TRANSCRIPTS
Friday, December 13, 2002

Allogeneic Stem Cell Update

Richard Childs, M.D.

Slide 1:

Thank you for that introduction, Dr. Thompson.
It's a pleasure to address this audience today. The work that I'm going to present to you has been a collaborative effort by several institutes at the NIH, including the NHLBI and the Urologic Oncology Branch of the National Cancer Institute.

Slide 2:

What I would like to do in the next ten minutes is discuss with you the results of patients with metastatic kidney cancer that have undergone allogeneic stem cell transplantation. And I would like to explain what the rationale has been for conducting such types of allogeneic-based immunotherapy, focus on the therapeutic efficacy of this approach from some of the preliminary data that we have gotten from the pilot trials conducted at the NIH, and from a number of other institutions in the USA.

And then finally, go over some of the mechanisms that contribute to the anti-tumor effects that we see that we call graft-versus-tumor, and look at some of the methods that we are hoping to develop in the near future for actually targeting this allogeneic immune approach.

Slide 3:

So in the next 30 seconds, I hope to convince you that performing allogeneic stem cell transplantation on patients with metastatic kidney cancer is actually not all that crazy of a thing to do. We know that kidney cancer is unusual among solid tumors in that clearly it appears to be immunogenic. Typically, it expresses high degrees of MHC class I molecules that are necessary for presentation of peptides required for T cell recognition. In addition, we know that kidney cancer can be responsive to immunomodulators like interferon alpha and interleukin-2.

Slide 4:

But there are a number of pitfalls of autologous-based immunotherapies, particularly the fact that the vast majority of patients treated with cytokine-based immunotherapy do not respond to that therapy. And those that do respond, more often than not, will have a partial response that is not durable.

Now, there is increasing evidence, particularly in the last two years coming out that patients with metastatic tumors may have dysfunctional immune systems. At last year's AACR meeting there were over 15 posters that went over data showing dysregulation in immunity involving T cells and natural killer cells in patients with cancer.

So there would be reasons to think that in the allogeneic study that there may be an advantage to transplanting a healthy immune system into a patient with cancer.

Slide 5:

Some of those reasons include the fact that we would now be supplying an immune repertoire from a patient that has never seen chemotherapy and also would have T cells that would be absent in a patient with kidney cancer.

And these include T cell populations that could go after antigens that we call 'minor histocompatibility antigens'. These are antigens that are derived from the degradation of proteins that are polymorphic between patient and donor. In the context of MHC class I expression, these can serve as tumor antigens.

If these antigens are expressed broadly on normal tissues and on tumor cells, then in the setting of graft- versus-host disease, they could serve as a tumor antigen. And if they were restricted to the tumor, they could serve as a tumor-specific antigen.

Slide 6:

And this is just an example of one of those experiments where we have been able to show that this minor histocompability antigen-specific T cell clone kills patient hematopoietic tissues and also patient tumor cells. This is a broadly expressed minor histocompatibility antigen.

Slide 7:

Therefore, in the setting of graft-versus-host disease, such antigens could be a target for a disease response.

Slide 8:

I'll quickly go over the approach that we and others have been using. The idea is as follows. You give the patient some type of preparative regimen that contains immunosuppressive chemotherapy, typically with the intent of knocking their immune system down to a level that would be sufficient to allow for take of the donor immune system that will be transplanted to the patient.

We typically mobilize the bone marrow immune cells of an HLA identical sibling (based on Mendelian genetics, each of the patient's siblings has a 25% chance of being HLA-identical) by giving them GCSF for five days. We then collect an allograft by apheresis (from peripheral blood). Then we infuse it intravenously into the patient on day 0. And then patients will typically have a mixture of both donor cells and patient cells. This is a condition that we called 'mixed chimerism'. It's an intrinsically tolerogenic state (tolerant of tumor). You rarely will see disease regression in this setting.

And through manipulating the immune system post-transplant, we can get that mixed chimerism to transition to full donor chimerism, where we only can detect donor immune cells. Some of the things that we do to do that are to withdraw immunosuppression post-transplant, or to give infusions of donor lymphocytes. And it is typically in that setting where we see disease regression occur.

Slide 9:

Now, this is the transplant algorithm that we have used at the NIH. We use cyclophosamide and fludarabine to condition our patients. Both of these drugs given in combination are extremely well tolerated. We infuse the allograft on day 0. Initially, we had used cyclosporin alone as graft-versus-host disease prophylaxis, but we had a high incident of GVHD, and we subsequently added additional immunosuppressive drugs mycophenolic acid, and more recently mini-dose methotrexate to prevent graft-versus-host disease.

And then depending on the patient's out post-transplant, depending on what their disease is doing, and what their immune system looks like, that dictates how rapidly we taper their immunosuppression. Our goal is to try to have all patients completely off their immunosuppression somewhere between 60 and 100 days post-transplant.

There is data from animal models that it's important that you withdraw immunosuppression early when host antigen presenting cells are available, so that you can prime the donor immune system to patient tumor antigens.

Slide 10:

So we learned very quickly that kidney cancer was indeed a target for an allo-effect. This is data from the first group of patients that we published in 2000. We treated 19 patients. These were all patients with cytokine refractory metastatic kidney cancer that was progressive, radiographically evaluable. We had 10 responders, 3 complete responders and 7 partial responders.

This shows the Kaplan-Meyer probability of a disease response, all patients, and then broken up into patients that never had a history of graft-versus-host disease, versus patients that had a history of graft-versus-host disease. So you can clearly see that the GVHD, although a complication which can be severe, and sometimes be even lethal, when it occurs in a limited fashion, can be a positive prognostic factor in terms of having a disease response.

Slide 11:

I want to show you a few examples of some of our responding patients. This is the first patient that we treated who had extensive metastatic disease involving the lungs. Needle biopsy clear cell carcinoma that had slow regression of disease.

Slide 12:

Day 30 CT scan showing no disease regression. Day 110 CT showing complete disease regression,

Slide 13:

now approaching five years post-transplant with no evidence of disease recurrence. This patient was refractory to interferon alpha.

Slide 14:

This is a patient that had bulky anterior mediastinal disease and hilar adenopathy, also IL-2 and alpha interferon failure, showing stable disease at 180 days post-transplant, and 270 days post-transplant, significant regression of disease.

Slide 15:

And this is finally a patient that had extensive pulmonary disease, who had immunosuppression withdrawn, and then received a bolus of lymphocytes from the donor that we had previously collected and cryopreserved. The patient then had regression of lung disease.

Slide 16:

There are now two groups this year that have published data showing responses in patients with metastatic kidney cancer, including Dr. Vogelzang's group from the University of Chicago, with Dr. Rinny where they had 4 out of 12 patients treated that had disease regression. They actually had 4 out of 9 responses if you look at the patients who engrafted.
And then the group from Milan, Italy reported in Blood this year, 4 patients out of 7 with metastatic kidney cancer that had disease regression.

Slide 17:

So to quickly update our experience, in the first 55 patients that we have transplanted, the major toxicity that we have seen has been acute graft-versus-host disease in 61 percent of the patients. Most of the patients we have been able to get through with immunosuppression to overcome their GVHD. We have unfortunately had 5 patients that died from transplant-related events, including 3 patients that died from GVHD, and 2 patients that died from infectious complications related to the transplant. One patient died of post-obstructive pneumonia, and another patient died from a line-related infection.

Slide 18:

This just shows events post-transplant. And I just want to focus on the fact that these anti-tumor effects are typically delayed. They usually don't occur until anywhere from three months to a year post-transplant. So it's very important that you be selective of the patients that you put on these studies, because if their disease is going to get out of control and get them in trouble in the first couple of months, then this approach will be of no value to them.

Slide 19:

In terms of the limitations of this approach, there are a number of them, including the fact that patients are required to have an HLA-compatible donor. That will limit this approach to about 1 in 3 patients with metastatic kidney cancer. Transplant-related mortality remains problematic, mostly a consequence of graft-versus-host disease. And this approach is a non-targeted type of immunotherapy. Graft-versus-tumor effects, as I said before, are delayed and tumor kinetics can be limiting.

Slide 20:

So in conclusion, for our patients with metastatic kidney cancer that have been treated with non-myeloablative transplantation, renal cell carcinoma appears to be a target for allogeneic immune-based immunotherapy. Partial responses and complete responses can be achieved in patients with cytokine-refractory metastatic kidney cancer.

The bad news is that the minority of patients will actually achieve a complete response, and we think that we need to focus on methods to turn our partial responders into complete responders. And one of the ways that we are looking at doing that is to try to develop tumor-based vaccine strategies to give patients post-transplant.

One of the approaches that we are looking at is fusing patient tumor cells to donor dendritic cells to vaccinate patients after the approach. And Ram Srinivasan in our laboratory, has some very nice in vitro data to show that these dendritic cell-tumor fusions in the allogeneic setting are much more immunogenic than they are in the autologous setting. And I hope to bring that to clinical trial within the next couple of years.

And finally, toxicity again, is the major limitation of this approach. And for that reason, we believe that patients should fail cytokines before they come to us, and that we need to be extremely selective in those patients that are put on these types of pilot studies.

Slide 21:

I'm just going to quickly flip to the acknowledgement slide, and thank all those people that have contributed to these studies, particular a number of fellows that have from Dr. Linehan's lab, who have done really excellent laboratory and clinical work with these patients.

Thank you for your attention.