ASCT Weakens CAR-T Therapy?

Why does an ASCT weaken CAR-T Therapy? This finding of the study linked below is damning enough for MM survivors who have had an ASCT as well as MM patients who are considering an ASCT.

But because all NDMM patients must consider sequencing of the many therapies they will undoubtedly undergo in their efforts to control their incurable blood cancer, it is important, in my thinking, to try to figure out why ASCT weakens CAR-T therapy.

According to research, autologous stem cell transplantation can weaken the effects of CAR-T cell therapy in myeloma patients. Why is this?

Possible reasons include:

Immune Suppression Post-ASCT:
- ASCT involves high-dose chemotherapy, which can significantly deplete the patient’s immune system. This depletion can reduce the ability of the CAR-T cells to proliferate and persist effectively, as the immune environment necessary for CAR-T cell expansion and survival may be impaired.
Altered T-Cell Repertoire:
- After ASCT, the reconstitution of the T-cell compartment can take time, and the newly generated T cells might not support the CAR-T cells adequately. This delay in immune recovery could limit the long-term persistence and functionality of CAR-T cells.
Impact on the Tumor Microenvironment:
- High-dose chemotherapy before ASCT can alter the tumor microenvironment, potentially leading to reduced antigen presentation or changes in tumor cell biology that make them less susceptible to CAR-T cell targeting.
Cytokine Dynamics:
- The cytokine milieu post-ASCT might not favor the activation and expansion of CAR-T cells. For instance, essential cytokines like IL-2, IL-7, or IL-15 might be reduced, hampering the effectiveness of the therapy.
Depletion of Supportive Immune Cells:
- Chemotherapy can deplete not only malignant cells but also supportive immune cells like dendritic cells and natural killer (NK) cells. These cells play a role in modulating and supporting CAR-T cell activity.
Regulatory T-Cell Expansion:
- ASCT can inadvertently promote the expansion of regulatory T cells (Tregs), which suppress immune responses. Increased Treg activity could dampen CAR-T cell function.
Timing and Sequencing Issues:
- If CAR-T cells are infused too soon after ASCT, the residual effects of chemotherapy and a weakened immune system might hinder their engraftment, expansion, and persistence.
Exhaustion of CAR-T Cells:
- In some cases, the stress induced by the high tumor burden post-ASCT or residual immunosuppressive effects might lead to CAR-T cell exhaustion, reducing their efficacy.

Clinical Implications: Understanding these mechanisms has important implications for the sequencing and combination of therapies in multiple myeloma. For instance:

Alternative Sequencing: Administering CAR-T cells before ASCT might improve outcomes by avoiding the immunosuppressive effects of chemotherapy.
Supportive Interventions: Using cytokine support or immune-enhancing strategies post-ASCT could help improve CAR-T cell performance.
Patient Selection: Identifying patients who might benefit more from CAR-T therapy alone versus a combination with ASCT.

When I underwent an ASCT in December of 1995, I did so because my oncologist told me that an ASCT was “potentially curative.” Two relapses and 15 long-term side effects later and I think that my oncologist was wrong.

But the larger issue illustrated in 8 reasons why an ASCT weakens CAR-t therapy, possibly, listed above, point to a basic fact of all forms of chemotherapy. And that is simply that it (all forms of chemo) weakens the patient’s immune system.

Consider taking a low-dose approach to your myeloma treatment. To learn more email me at David.PeopleBeatingCancer@gmail.com

Thank you,

David Emerson

MM Survivor
MM Cancer Coach
Director PeopleBeatingCancer

Prior ASCT May Impact Outcomes of CAR T-Cell Therapy in MM

The median progression-free survival was 9.9 months in patients with history of transplant and 16.1 months in patients who had not received a transplant.

BCMA-directed chimeric antigen receptor (CAR) T-cell therapy may be less effective in patients with multiple myeloma (MM) who have previously received high-dose melphalan and an autologous stem cell transplant (HDM/ASCT), a new study suggests.

Researchers found that MM patients with a history of HDM/ASCT had significantly shorter progression-free survival (PFS) after BCMA-directed CAR T-cell therapy than patients who had not received HDM/ASCT. These findings were presented at the ASH Annual Meeting 2024.

The researchers evaluated 158 MM patients treated with a BCMA-directed CAR T-cell therapy, including 81 patients who had previously received HDM/ASCT and 77 patients who had not. Patients with a history of HDM/ASCT were significantly younger than patients who had not received HDM/ASCT (P =.009). In addition, patients with a history of HDM/ASCT were more likely to be men (P =.04), had a longer median time from diagnosis (P <.001), were less likely to have high-risk cytogenetics (P =.04), and had a lower median platelet count (P <.001).

The CAR T-cell therapies patients received were idecabtagene vicleucel, ciltacabtagene autoleucel, and anitocabtagene autoleucel. There was no significant difference in the type of CAR T-cell product received between patients who had a history of HDM/ASCT and those who did not.

There were no significant differences in response between the groups. The overall response rate was 83% in the transplant recipients and 88% in the patients who had not received a prior transplant (P =.37). Rates of complete response were 40% and 48%, respectively (P =.12).

Similarly, there was no significant difference in overall survival (OS) between the groups. The median OS was 34.2 months in transplant recipients and was not reached in patients who had not received a prior transplant (P =.43). The 18-month OS rates were 49% and 58%, respectively.

On the other hand, patients with a history of HDM/ASCT had significantly shorter PFS after CAR T-cell therapy. The median PFS was 9.9 months in patients with a prior transplant and 16.1 months in patients without a prior transplant (P =.011). The 18-month PFS rates were 27% and 47%, respectively.

In a multivariate analysis, prior HDM/ASCT was independently associated with significantly shorter PFS after CAR T-cell therapy (hazard ratio, 1.69; 95% CI, 1.09-2.61; P=.02).

When the researchers looked at the individual CAR T-cell products, they found that prior HDM/ASCT was associated with significantly shorter PFS among patients who received idecabtagene vicleucel but not among patients who received ciltacabtagene autoleucel or anitocabtagene autoleucel.

Among patients who received idecabtagene vicleucel, the median PFS was 9.2 months in patients with a history of HDM/ASCT and 14.7 months in patients without a prior transplant (P =.015). Among patients who received ciltacabtagene autoleucel, the median PFS was 10.3 months and 12.1 months, respectively (P =.86). Among patients who received anitocabtagene autoleucel, the median PFS was 29.3 months and 34.3 months, respectively (P =.35)…”

ASCT Weakens CAR-T Therapy ASCT Weakens CAR-T Therapy

Michel Pisano says 4 weeks ago

From my understanding, HDM/ASCT is still the standard first line treatment because it yields the longest median PFS, 50 months for eligible patients. This research then sheds light on the choice of second line treatment. Anitocabtagen autoleucel is best. Please confirm or correct.

David Emerson says 4 weeks ago

Hi Michael- you are correct that ASCT is the FDA approved SOC and can yield the longest first remission. Keep in mind however, that the study linked in the post confirms that ASCT weakens the CAR-T procedure. Also, ASCT results in more toxicity, more short long-term and late stage side effects. Questionable therapy that does NOT result in a longer OS aka length of life.

Recently Diagnosed or Relapsed? Stop Looking For a Miracle Cure, and Use Evidence-Based Therapies To Enhance Your Treatment and Prolong Your Remission

ASCT Weakens CAR-T Therapy?

According to research, autologous stem cell transplantation can weaken the effects of CAR-T cell therapy in myeloma patients. Why is this?

Prior ASCT May Impact Outcomes of CAR T-Cell Therapy in MM

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